Dna Dbpooltioll
--------------------~
Oin. I'tlarmacokinct. 19 (6): 434-461. 1990 0312-S96J!90/0011 ..(4)4!S 14.00/0 C Adi s Intemationall.imited All ri&hIS reserv<":d.
~- -
Clinical Pharmacokinetics of Ciprofloxacin Kyle Vance-Bryan, David R.P. Guay and John C. ROIscha/er College of Phannacy, University of Minnesota, Minneapolis, Minnesota. and 51 Paul-Ramsey Medical Center, 51Paul. Minnesota. USA
Contents
Summary .................................................................................................................................. 434
I. Pharmacology of Ciprofloxadn ..... "................... 1.1 Chemistry ...... 1.2 Mechanism ... 1.3 Resistance ......
........ ...............
.................
. ...436 .. 436
................... ..................
1.4 Spectrum 2. Phannaooic.inetics of Ciprofloxacin 2.1 Assay ........................... 2.2 Absorption ................................... . 2.3 Di$lribution 2.4 Metabolism ................ .................. 2.S Excretion .. 2.6 Multiple Dose SlI,ldies ................................. ..................... . 2.7 Special Population Phannacokinetics ........ 3. Drug Interactions and Adverse Effects .............................. 3.1 Drug·Drug lnteractions .................................... 3.2 Advt'T"$C Reactions ...... ................................................. ..................
.. 436 437 440 .. 440 .440 .. 441
..... .. 450
...................... .. 450 ......... 451
'" '"
..453 ......... 453
Compared wi th nalid illic acid, ciproflOllacin is representative of a newer, more potent class of quinolones, lerm«l the fluoroquinolones. It is available in both oral and paren teral dosage forms. The primary target of quinolone activity appears to be the bacterial DNA gyrase enzyme. which is a me mber ohhe class ortype II topoisomera.ses. Bacteria do not acquire resistance to fluoroquinoloncs through mechanisms that are plasmid or R-factor mediated and, additionally, the quinoloncs do not appear to be vulnerable to dCJradation by bacterial inactivating mechanisms. Ra ther, bacterial resistance to ciprofloxacin occurs ei ther through chromosomal mutation in th e target enzyme DNA gyrnse or through muta tions that aller drug permeability in to the bacterial cell. Ciproflollacin and the fluoroquinoloncs in general are no more likely to select resistant mutan ts than are am inog.lycosides or P-lactam antibiotics. Ciproflollacin d isplays if! l';(ro activity agai nst most Gram-negative and many Grampositive pa thogenic bacteria, many of which are resistan t to a wide range of antibiotics. This finding is of considerable potential clinical significance. High pressure liquid chromatography (HPlC) and microbiological agar diffusion as-
(,hmcal PharmacokinellCS
ofCiproflo~acln
435
ha\c been rOUllncl~ used 10 quanllfy ClprOnOllaCln concenlrations in biologJcal fluids. Bolh melhods arc reproducIble and accuralC for serum bUI HPlC is recommended for Olher speCImens b..'Cause of Ihe prese'lCe of microbIologIcally ani"e metabolnes. Absorpllon afler oral admlnlSlrallon IS rapId and can be sallsfaClOnl) described as a lero-order process: peak serum ClproflOllaCln conccn trall ons (C rna ,) arc reached in appro.\ lnlatcl) I to 2 hours. Concomitant admlnlSlrallon of food docs not cause clinically s.gnlflcant ImpaIrment of absorpllon and rna) oc helpful in mmlmising gastne dislress caused b) the drug. A Imear relallonshlp ocI"een serum Clpronoxacm concenlratlOnS and the dose admlnlstcred Clther orall) or Intra\enousl} has ocen reponed. The absolute bloova.labllll) ofclprono~aem IS appro.\lrnalcl} 70%. The volume of dIs In bUll on IS large wllh a steady-slale range after oral or Intra\enOUS dOSing of 1.74 to 5.0 ljkg renecllng penetrailon of Ihe drug IntO most tissues. Nonrenal clearance aecountsfor apprOlllmatel) 33% of the dlmmahon of Clproflollacm: to date. 4 metabolites havc been identified. A firsl-pass effect has been reponed but IS thought to be clinically Unlmponanl. Faecal recovery of Clprofloxacm accounts for approximately IS'*' of an Intravenous dose. Nonrenal ehmmallon mcludes metabolic degradation. biliary excrellon and tran51ummal secre1l0n across the enleric mucosa. Glomerular fill ration and tubular secretion aecount for approximately 66% of the 10lal serum clearance. Thc tcrmmal dispoSitIon half-life (I,.,) is about 3 10 4 hours. Pharmacoklneilc studies afler muillple mtravenous doses of clprofloxacm have not reponcd $ignitieant diifer<:nc<:s 10 terminal dIspoSItion half-lives or s)stem le clearances bel .....ccn Ihe first and the last dose. The pharmacokinCIlCS of Clprofloxacin in the elde rl y are sIgnificantly dlffrrent from those obscf\ed In the young: thr elderl) ha\e a reduced rrnal dearance. a sIgnificantly greater area under the concentratIOn-tIme curve (AUC). a larger C rna ,. and a prolongcd t.·,. Sc\CraJ mvesllgatOrS have suggested Ihat dosage mtenals shorter than 12 hours be a\olded 10 thr elderl}. The pharmaeokmellcs of clproflo;r.;acin in patients wllh CySIIC fibroSIS do not differ SIgnIficantly from those of healthy conlrol populallons and. as a result. dOSing regImen alterations arc nOI reqUITed m pallcntS with eyslic fIbrOSIS. In pallents wlIh \aT}lng degrees of renal dysfunction. the pharmacokinetIcs of ciprOflo~aeln arc Slgnlficantl> altered: the I'I:! In end-stage renal disease IS appro;r.;,matcly t"icc that of hcalth} controls ('" 8h). The observed AUC and C ma , may also be elevated In thcse pallents. A ",de varlabihty In the t,:, of ciproOO)(3eln has been observed among pallents ..... ith S('\ere renal failure. resulting in the recommendation Ihat changes be made In the dally dose ralher Ihan the dOSing .ntcrval In order to achlCvc drug coneentrations comparable wlIh those obsened in normal renal functIon. The cllmcal Impacl of eh ronlc ambulatory pentoneal dlal)sis or haemodlal}sls over a 4-hour period on the pharmacoklnClies of ciproflo;r.;ann IS nOI significant. and Iherefore dosage supplementallon after or during these procedures IS nOI necessary. L,,'er dysfunction also appears to exen liule effe(;t on eiprono;r.;acin pharmacoklnellCs and dosage adjustments arc not rcrommended. The co noomitant oral administration of magnesium-. aluminium-. or calcium-containing antacids. 5ucralfate. Iron preparations and mulli vitamins cOntalO1Og ZIO' significa ntl y reduces the absorption of ci pronoxaein. Ciprofloxacin reduces the metabolism of theophylline by appro;r.;imately 15 to 30%: caulion 15 therefore advised when using any fluoroquinolone in combinalion with ;r.;a nth ine compounds. Case repons havc documented increases in prolhrombin limes among patienlS receiving warfarin and eiproflo)(3cin concomitantl y. Adverse reactions associaled wilh clprofloxacin administrallon arc generally mild to moderale and usually do not result in termination of Iherapy: thc worldwide incidence is in the range of 4 10 8%. which is similar to that reponed for Olher fluoroqUlnolones. The most commonly reponed adverse reactions involve eilher the gaSt rOlOteslinal tract (nausea. vomiting and diarrhoea). melabolic or nutritional disorders. or the eNS. sa~s
Clin. PhQrmQcokinft. It} (6) 19IJ()
1. Pharmacology 0/ Ciproflo:cacin 1. 1 Chemistry
o
" ':(:OCOOH
"",""''"\ ~ I I --./ N
l::.
(M2) SUfo.oiprofloxacin
o
"
F~COOH
H['N0) '--./
6'
L N
(M3) Oxo<:iprOfloxacWl
fi ~N0)
'~COOH
'--./
1
(M4) FOfTTIYk::iprofloxacin
Fig. 1. Chemical structures or cipronoxacin and its metabolites.
Ciprofloxacin is a I
Clinical Pharmacokinetics of Ciprofloxacin
of quinolone activity is the DNA gyrase enzyme, which is a member of the class of type II topoisomerases, This enzyme is required for DNA repli. cation, transcription o f certain operons, repair and recombination (Orlica 1984; Gellert 198 1; Gellert ct al. 1977; Hooper et at 1987; Sugino et al. 1977; Sutcliffe et al. 1989; Wang 1985), In 1';t,O, the quin. olones inhibit gyrase-mediated DNA supercoiling and promote double·stranded DNA breakage at specific sites (Fisher et al. 1981; Gellert et al. 1977; Morrison & Cozzarelli 1979), As pointed out by Hooper and Wolfson (1988), scveral additional and poten tially important issues concerning the action of quinolones remain to be explained. In y;'ro and in I'il'o assays designed to assess the inhibition of DNA supercoiiing by quinolones have demonstrated that drug concentrations wilh this effect are substantially greater than the minimum inhibitory concentrations (MIC) for bacterial growlh (Gellert et al. 1977; Miller & Scurlock 1983; Yamagishi et al. 1981 ; Zwccrink & Edison 1986). These findings and other observations (Kreuzer & Cozarelli 1979; Snyder & Drlica 1979) have led to the hypothesis that nalidixic acid, and presumably other quinolones, acts in intact bacteria principally through the formation of drug-enzyme-DNA complexes that fun ction as poisons. as opposed to si mple inhibitors of DNA supercoiling or other enzymatic activities (Hooper & Wolfson 1988). 1.3 Resistance In contrast to other antibacterial classes such as the penicillins. cephalosporins or aminoglycosides, bacteria do nOI acquire resistance 10 the fluoroquinolones that is plasmid or R·factor mediated (Hooper et al. 1987). Although the clinical signifi. ca nce of plasmid elimination from bacteria is un· clear, ciprofloxacin administration may result in both Ihe elimination of antibiotic resistant plasmids, a phenomenon referred to as plasmid curing, and the inhibition of conjugational plasmid transfer (Hooper et at. 1987; Weisser & Wiedemann 1985, 1987, 1988). The quinolones are not thought
437
to be vulnerable to degradation by bacterial inactivating mechanisms. To date. only 2 mechanisms have been discov. ered that ca n result in the development ofbaclerial resistance to quinolones. The first involves chromosomal mutation in the target enzyme DNA gyro ase. and the second involves mutations Ihat alter drug permeability (Aoyama et al. 1988; Hane & Wood 1969; Hirai et al. I 986b; Hooper et al. 1986, 1987). In general. the frequency of spon taneous si ngle· step mutations that result in resistance to fluoroquinolones is at least 300-fold lower than that observed with nalidixic acid or oxolynic acid (Neu 1988). In addition. it has been reported that the fluoroquinolones are no mo re likely to select resistant mutants than are the aminoglycosides or fjlactam antibiotics (Sanders et al. 1984). Selection for resistance to all of the nuoroquino10nes after serial passage of organisms in the presence of increasing concentrations of drug has been demonstrated (Barry & Jones 1984; Chin & Neu 1983, 1984; Eliopoulos et al. 1984, 1985; Husson et al. 1985; King et al. 1984; Kumada & Neu 1985; Reeves et al. 1984; Tenny el al. 1983). The resist· ant strains that result after serial transfer often exhibit cross-resistance to other quinoiones (Barry & Jones 1984; Chin & Neu 1983: Cull mann et al. 1985; King et al. 1984; Sanders et al. 1984: Tenny et at. 1983). In the clinical selling. although reported infrequently to date, resistance to all of the new quinolones has been encountered. particularly for isolates of Pseudomonas aeruginosa. Serratia marcescens and Staphylococcus aureus (Bender et al. 1986b; Follath el al. 1986; Mehtar et al. 1986; Scully et al. 1986). Cross-resistance to other classes of antimicrobial agents, and specifically to fj- Iactam antibiotics. has been shown infrequently to occur simultaneously with the developmenl of resistance 10 fluoroquino10nes (Sanders et al. 1984). This resistance appears to be related to changes in outer memo brane proteins involved in permeability. In gen· eral, although cross-resistance between the flu oroquinolones has been well documented (Chin & Ncu
438
Clin. PhurmacQkmN. / 9 ( 6) 1990
T, , " I. Summary 01 pooled in vitro minimum inhlbllOly concentration IJUsceptlbilily data
org.anlsm.
Mocroorg'rlI'm
NO. 01
A..-obk: Gla m (+1 cocci __ M.thCillin-resi,tant Sfaphylococc/n _ _
Sl~1ocoeeut eplfWmidi$ St~~ IINmo/ytICU$ St~lococcus s.p#opIIyUcu&
St'Pltylocoecus 'PI) .
SIr,p!ocoecus group " ~,) Sireptocoecu. group B (agalactl,.) Streptococcus group 0 (faeca/i.) Str.",OCOCCII. prtfNmoniH
A.,obI<: Gram (+) rods CorynebKrerium 'PI). C<>tynet>act.,ium JI( GMclfHNe/l• ...1IgI~j.
U'/lKia monocyI'ogenes NOCNdlll Ulerolda Aerobic O,..m (-) rod. Cltroo.ctfJ( d/lletsus CllrobaCleI Ir""TldI CllrotMCler 'PI). EnlfHot>actfH H~S
En/I,ot>acr., cloeelle EntfNObM:;/er spp.
E,ch«lcllJe coli H.W.MwI
-"~/.oxytou
~"spp.
M~glfWIIl.
morQMlii
Prol_ mJr.tJ/lI, Proteus vulgMI.
ProtlUl Ipp. ~jndole +) Provldencl. rel/getl Prcwldenc'- .IUIllf/1
Provldenclll '!)p. Sal_II. MIIerirldis S./1TIOIIeI1. pv.typhi B. SaI~1II typhi
SalmoneIIII typllif'l1Ufium Sa/moneIlII llquel~ SltImoneIIII spp. ~lIIspp.
S.",II,
Serr.'11I
",..-cUCIMS
,pp.
YfKllni. enr.roco/lrk;.
"'Coo
.
"""
237
O. I~
0.25-1 0 .5-1
'50
0.(13.1
O.2S-O.S
0._
0.' 0.' 0.'
Isolates
Sl~ylococcu.
"'C
tor clproflo)(itCM"I against pall'lOg8niC ITIICro-
,
""
69 39
'"
'"
727
"
"" " ,,." 75
..
>3, "
'"
.
'" " '" '" '" ". " '" ". 28'
70 70 7
""'"
0.015-8
0.125-4.5 0.125-1
0.2-2
0.5-2
0.12-25
0.5-2 0.5-6.3
0._
1-3.1
0.05-<1
0.074 0.5-1
0.008-2
0.5-2
,.,
0.1·2
0 .•·2
0.06-1
0." "
•
O.O,5-{).02 0 .015-0.12
O.~-o.5
0.004-0.12 0.03-0.12
0.005-4 O.()()S.1
0.004-\ 0.002-\ 0.06-0.125
<0.008-4 0.005-(1.5
O.03-().12 O.Q08.0.25
0.009-0.5 0.125 0.03-0.06 0 .1)26.0,2$
"• ",
,, ,, 9
" ,,, , , 7
•
,• 7
",, ,
O.OIS-O.5
<0.002-0.5 0,(I()8.O.5
O.OIS-O.25 0.03-0.12
<0.008-0.12 0.008-0.25
O.ON).06 0.03-<0.06
0.008-8
0.2-2
", ,
0.005·8 0.0'3·' 0.008-0.125
0.25-2
7
0.016-0.25 0.06
.
0.06 0.06-0.125
<0.002-0.05
0.01-0.125
77
0.002-0.195 0.015->2 0.006-2
"
ref,rences
0.002"",
0.01-<0.091 0.016-(\,125 0.06-0.125
'", '" '" '"
NO. 01
O.O,6-().125
O.OO8-{1.195
0.12S 0.02-0.097
0.008-0.097
0.12·' 0.028-0.5 0.009-0.097
7 7
7
, ,, ,, ,,•
•
439
Clinlral Pharmaco k ,nCI IC'S ofCIpr otloll 3cin
Table I. Contd Microorganism
No. of Isolate s
Nonfennenlor, - Jerobic Gram ( - ) rod, ACin&lobacler caJcoacelicus AcmelOO8Cfer spp. Pseudomonas aerugmO$1I PselJdomonas capacla Pseudomonas rrnlirophilia Pseudomonas flllOra$CenS Agrobac/er spp Alcllilgenes spp Elkenella corrodens FlavobactelllJm menmgosepllClJm
Aerobic Gram ( -) CoecObllC il!i Brucella meMensls Haemophllus ducre'JI Haemophllus mlllJenzae
Hllemophllus spp P;ul..,,,..,I.. m"ltoclfJa Anlle,obes AerobiC Gram (- ) COCCI Btanhllmella CII/llrrhlliis
NelS5MII menrngltidi$ Neissellll gonorrlloeae N6ISSlIfllI spp
Anaerobes Anaerobic COCCI Bacreroldes frllglils BacteroIdes spp CIOSindllJm dlfflclle CIOSiJldium spp
"" 25
20
"" 5
68
SO
'", " " " '"" '" '" 00
60
SO 20
FusoDBCleflum Eubllcrerrum V6IlIon&l/a spp
Mycobacleria Mycobaclfmum ltV/um Mycobaclfmum
... ,,.."
c~lonalt
MycOf)BClltllum Ior/Ultum MycotJaclerlum inlracellu/a,e Mycobacterium kansas;; Mycobacterium luoe'clJlosis
" "
32
'"",
,,. 3
"'C range 005·1 0004·6,3 0006·2 01·63 0015·8 0.05·31 003·006 0.03·8 0.25·16 0125·1 05·1 0008·0.03 0004·0.03 0004·0.008 0.004 0.03
Mycoplasma hominis Ureaplasma lJfealyticum
27
""
No. of
range
re ferences
011·0.5 006·16 009·1 '3 0.49·8 05·3.1
,,
0.06
, 003 0.007·0.016
000' 0016
, ", 3
,,, 3
,,,
<001·0,06
005·006
,
<0.0005·0.0 1 <0.0005·0.25 <0.002·0.05
0004· <0.01 0.002·0.25 0002·0,008
,,
0.03·1 6 <0,01·32 0. 1·32
0.8·8 0.8·16
'·32
32
,.,
3
,3
,
3
,,,
0.12·64 0.03- 4 0.5·2 0 12·025
,,.,
0.25- > 16 0.125·> 16 0,016·2 2·> 16
,
,.,
" ,",
0. 125-5
1.4.3
3
0. 5·2 0.25-0.5 0.5-> 64
,.,
,
0.5
MiKellen _, Chlamydia trachoma/I$
M!Cgo
025·32
0.12·0.25
>8· > 16 0125·2
2·32
3
3
,
,
References: Arpi el al. (1987): Aockenltlaler el al. (1986): Barry et at (1 984): Ba uernfeind & Petermuller (1983); Caekenberghe & Pattyn (1984): Chin & NelJ (1 984 ): Floyd· RelSing et al. (1987); Goossens et al. (1965): Hoogkamp. Korsta n,a (1 984): King et al. (1984); King et at (1985): Urnb et al. (1987): Manek et al. (1986): Malulli at al. (1990); Reeves et a l. (1984): Smith (1986). Turgeof1 at al. (1 987): DaImee & Ave sani (1986). AbbfevietioM: MIC '"' minimum Inhlbilory concentra tion: MICgo '"' MIC for 9O"iI. 01 strains.
440
1983, 1984; Tenny el at 1983), the development of cross-resistance between fluoroquinolones and other classes of antibiotics has nOI been widely reported and the clinical significance at this time is difficult to determine. 1.4 Spectrum
Ciproflolt3Cin has been shown 10 be very active in )'Uro against a wide variely of pathogenic bacteria, including some Gram-positive and most Gram-negative organisms (table I). More than 95% of the microorganisms tested in several large studies were inhibited by the drug at concen trations .=s; 2.'1g/L (Barry el al. 1984; Fass 1983; Hoogkamp.. Korstanje 1984). The in ,·juo MIC susceptibility breakpoints for ciprofloxacin were preliminarily established as .l!O I mill for susceptible microorganisms, 2 mg/l for those moderately susceptible and ~4 mg/L for those resistant (Barry et al. 1985; Grimm 1987; Sanders et al. 1987). The current M IC breakpoint recommendations of the National Committee for Oinical Laboratory Standards (NCCLS) (April 1990. unpublished communication] are identical to the preliminary recommendations. Some investigators, however, have suggested that it may be more appropriate to conside r M IC values of~2 mg/L as indicative of resistance. particularly when referring to Gram-positive isolates (Arpi et al. 1987; Barry & Jones 1987). Also, because ciprofloxacin concentrates in the urine, the use of these breakpoints in detennining the susceptibilities of urinary tract isolates would be inapp ropriate. Disc diffusio n breakpoints, as recommended by the manufacturer (PDR 1990), using a 5.11g ciprofloxacin disc are -'l > 15mm resistan t, 16 to 20mm moderately susceptible and i!l 2lmm sensitive. Ciprofloxacin exhibits excellent activity against Gram-negative aerobes, moderate activity against Gram-posi tive aerobes and very poor activity against most anaerobic organisms (King et at. 1984; Reeves et aJ. 1984) (table I]. Ciprofloxacin has, in general, good in v itro activity against many different pathogens resistant to a number of antibiotics, including methicillin-resistant S. aurnJs, Emero-
Clill. /'tIarmacokmn. 19 (6) 199()
rueter aerogenes, E. cloacae and Citrobaaer frl'Undi (Arpi et al. 1987; Chin & Neu 1984; Reeves et al. 1984; Shalit et al. 1990). In contrast to the aminoglycosides and tJ-lactams which have activity against bacterial cells in the growth phase, ciprofloxacin usually is rapidly bactericidal in "itro and in fi~'o against both growth phase and stationary phase cells (Chalkley & Koomhof 1985; ingennan et at. 1986; Reeves et al. 1984; Zeiler 1985; Zeiler & Grohe 1984) with the exception of S. aureus. With the exception of some strains of P. aeroginosa, staphylococci, Proteus sp. and Providencio sp., ciprofloxacin does not demonstrate tolerance as defined by the ratio of minimum bactericidal concentration (MBC) to MIC being greater than or equal to 32. Against most aerobic Gram-positive and Gram-negative bacterial pathogens, the MBC is within 2 standard dilutions of the MIC (Auckenthaler et al. 1986; Campol i-Richards et at. 1988). A postantibiotic effect of ciprofloxacin has been demonstrated in vilro and in some instances in vi~'o against many enterobacteriaceae, P. aeruginosa and S. aureus, but not against the enterococci (Chin & Neu 1987; ingennan et aJ. 1986).
2. Plrarmacokinetics 0/ Cipro/loxacin 2.1 Assay Two types of assay systems have been routinely employed to quantify ciprofloxacin concentrations in biological fluids: they are high pressure liquid chromatography (HPLC) and microbiological agar diffusion assays. Several HPLC methods have been reported for quantitative analysis of ciprofloxacin concentrations. Some methods utilise UV (ultraviolet) detection, while other.;; use fluorescence detection (Awni et al. 1987). Modified HPLC procedures are also capable of detecting concentrations of the metabolites of this drug (Bomer 1986; Gau et al. 1986). There have also been a number of reports of microbiological assays using different test organisms including Escht>richia coli (ICB 40(4), KIth-siella pneumoniae (ATCC 10031) and Bacillus sublilis (ATCC 6633). These microbiological assay
Clinical Pharmacokinetics of Ciprofloxacin
techniques have employed a variety of different media and pH conditions (Brogard et at. 1985a; Gonzalez et at. 1985a; Hofl'ken et at. 1985; Jehl et al. 1985: Joos et al. 1985; Wise et at 1984). Most investigators have reported that the correlation between ciprofloxacin concentrations determined by HPLC versus microbiological assay is good for serum specimens and adequate for urine. suggesting that either assay technique may be clinically useful for measuring ciprofloxacin concentralions from these 2 fluids (Brogard et al. I985a.b: Jehl et al. 1985. 1987; Vallee et al. 1986). In contrast. correlat ion is poor between the 2 methods with respect to ciprofloxaci n concentrations determined for bile specimens. For these. concentrations measured by microbiological assay are significantly higher than those determined by HPLC (Brogard et al. 1985a,b; Jehl et al. 1985). This discrepancy may be explai ned by the presence of microbiologically active metabolites of ciprofloxacin. Some investigators, in fact. have reported significant differences between HPLC and microbiological assay determinations of urinary ciprofloxacin concentrations, and have concluded that this difference is probably due simi larly to active metabolites (Borner 1986: Borner et al. 1986a: Joos et al. 1985). Tanimura et al. (1986) have demonstrated that 4 metaboli tes of ciprofloxacin ha ve activity against E. coli Kp. Zeiler et al. (1987) have reported that the antibacterial activity of metabolite I (desethylene-<:iprofloxacin) was comparable with that of nalidixic acid, metabolite 2 (sulfo-ciprofloxacin) had very weak activity and metabolite 3 (oxo-ciprofloxacin) was similar to norfloxaci n in activity. This same group of investigators stated that they do not believe that the antibacterial activity of the cumulated metabolites of ciprofloxacin account for the difference between the values observed between microbiological assay and HPLC, on the basis of the observation that the microbiological activity of unchanged ciprofloxacin greatly exceeds that of the metabolites. These investigators concluded that other factors (such as variations in the different assay methods or preparations of specimen dilutions) probably account for the discrep-
441
ancies between microbiological and HPLC data. Because of the inability of the microbiological assay to differentiate between unchanged ci profloxacin and its metabolites, it seems reasonable \ 0 conclude that HPLC is the preferred technique for determining ciprofloxacin concentrations in bile and probably urine, whereas either technique is appropriate for determination of serum ciprofloxacin concentrations. Finally, of interest is the fact that the fae<:al elimination ofciprofloxacin assayed by HPLC has been reported to be significantly higher than that found by microbiological assay, The cause of this discrepancy is not clear and the possibility that the antibacterial activity of ciprofloxacin might have been inhibited by a factor present in the faeces seems to have been ruled out (Brogard el aL 1985a). 2.2 Absorption Table II is a summary of the pharmacokinetic data for ciprofloxacin collected from several investigations using oral administration. The absorption of ciprofloxacin after oral administration is rapid and. although the influence of disintegration! dissolution processes on ciprofloxacin absorption is unclear, the absorpt ion phase can be satisfactorily described by a zero-order pharmacokinetic eq uation (Tartaglione et al. 1986). The time (t max ) to reach peak serum concentrations (C max ) is approximately I to 2hours (Bergan el al. 1986a,b: Borner et al. 1986a: Esposito et al. 1987; Gonzalez et al. 1984), The presence of food has been generally shown to prolong t max and to possibly decrease C max (Borner et a!. 1986; Dan et al. 1986). At least I investigator has reported, however. thai food has no effect on either parameter (Frost et al. 1989). Although an obvious explanation accounting for the different results among these studies is lacking, possible answers include small study populations and nonuniform experimental methods. Because no studies have demonstrated that food significantly reduces C max , area under the serum concentration-time curve (AUC) or urinary recovery of ciprofloxacin, the concurrent ingestion of food
250
12.2 11.8
t8.8
265 1.90
282
1.16
708
7.38 14.68
1.96
2.16
3.76 3.62
23 NA
1.00
1.13
1.25
1.19
1.26
150
5(M)f5(F)
1."
IOqI2t1 1.5 1.11 1.0!
lq12h NA lJq12h NA 1 1.5
NA
1.07
3.02
1.18 0.94
1.19 0.88 1.14
\ .11
4.23 3.58 6.18 8.11
0.31
1.'"
083
1.51 1.91
9.'
9.8
2.8
2.3
5.3
52
"' NA
' .1
11 .61 9.9
.ro
1.49
1.29
0.48
0.38
I
0.81
13q 12h
0.93
1.45 1.80
1.0
1.9
15.3
NA NA NA NA NA
2.141.78-
NA NA
NA NA NA NA NA NA NA NA NA NA NA NA NA NA NA NA
2.66
4.65
3.52
3.52
3.52
NA NA NA NA
NA NA NA NA NA NA NA NA NA NA NA NA
3.53
3.'" 3.'"
4.62
3.81
NA
4.18
13.93
NA NA NA
NA
NA
NA NA
3.16 3.11
NA
NA
NA
NA NA
(L/kg)
Vd,l
10.00
3.38-
16.6
12.9
7.'
3.7
2.91 0.28 0.49
083
,!
" .. (mg,L' hi (L/kg)
AUC
1.38
0.59
12(M) 250 12(M) 250 6(M)'6(F) 500 6(M)/6(F) 500 6(M)/6(F) 100 5(M)/5(F) 250 5(M)/5(F) 2SOb 5(M)/5(F) 500
81M) 150 6(M)/6(F) 50 6(M)/6(F) 100 6(M)/6(F) 150 12(M) 500 12(M) 500 l(F) 100 81M) 100 8(F) 250 8(M) 250 1(F) 500 8(M) 500 8(F) 100 7(M) 100 6(M) 500 12(M) 250
100><2
0.69
3.51 1.18
1.'"
""""
2.26
OM) 6( MlI6(F)
1.33
0."
3.38
2."
1.60
0.76
(ITlQ,L)
c...
0.81
1.80
1.67
1.12 1.46
(h)
!ma.
250
250><4
1000
250><3
750
250><2
500
No. 01 doses
500 6(Ml/6(F) 500 200 OM)
II(M)
11(M)
OM) 11(M)
(mo)
No. (sox) Dose
Table II. Pharmacokinetics 01 ciprolloxacin after ora! adminislra!ior1
NA NA NA NA NA NA NA
3.95 5.65
4.31
NA NA NA NA NA NA NA NA NA NA NA NA NA NA NA
NA NA NA NA
NA
NA
NA NA
Vb,l (L{IIg)
3.31
3.15 5.42
5.33
4.39
4.11 6.51 2.5 2.5
3.71
3.9
3.63
3.08 4.07 2.99 3.70 3.17
3.57
3.3 ' .0 2.66
4.15
' .09
5.19 3.44
85.52"
59 .10" 69.83-" 13.15-
5650'
52 .09" 52 .09"
41 .8547 .1&'
68.11 66.1250 .5161 .13-
62.7670.5861.12-
59.5S-
61.4142.3726.60" 67 .3411.58-
52.63-
50.' "
42.20
39.10
4U6
4.12 4.11
5H8
73.98-
60.24-
58.14 -
23.04
20 .28 16.5-4
18.06 20.40
NA NA
21 .6 25 .5 26 .8
29.0 33.'
42 .5
21 .8
NA NA
NA
17.6314.8514.70"
30.8
19
27 27
27
'" " " "
46.0
38.'
330
35.3
35.6
NA
NA NA NA
27
28.5
39.5
44 .0
38.'
'.<",
NA
18.10" 18.51-
19.73-
20.53-
23.2418.8124 .41 -
NA NA NA NA NA NA 2.3.54-
NA
21 .48
22.86 23.76
18.96
21.96
26.62
23.70
57 .W &5.76-
(L{tl)
CL",
(LI"I
CL"
4.11 3.69
.3
' .9
' .1
' .1
(h)
,-
NA
52
NA NA
..
NA NA NA NA
63 NA NA NA NA NA NA NA NA NA NA NA NA NA
69.\ 77
69 .0
55 .6 55 .6 55 .6
NA
NA
NA NA
(")
,
HPLCII HPLCII
HPLCII HPLCII HPLCII
BIO!O BloW
HPLct
HPLC9
HPLC7
B.' HPLct
HPLC1 HPLC7
HPLC7 HPLC1
HPLC1
HPLC1 HPLC 7
BioG
,
.."""
B"" B""
HPLC·
HPLC4
HPLC3
HPLC3
HPLC2
B.'
Bio! Bio!
Assay
~
~
e
~
[
Q
;
~
t
"""
7ql2h 13q12h
7q l 2t1 13q12h
c..... ..
, 00
,,,
'58
'" '" '00
3.41 4.21 4.15
2.89
2.77
2.60
'35
1776
"" ""
1241 13.94
"60
'"'" ,,,
85'
1220
261 1.42 1.37
'99
• 80'
",
127
'00
1.21
' .23
2.91
283
NA NA NA NA NA NA NA NA NA NA NA NA
'78
'99
'00
NA NA NA NA NA NA NA NA NA NA
,." NA
NA NA
" NA NA NA NA NA NA NA NA NA NA NA NA
NA NA
NA
,
'92
'",3< '"
'"
.. ."
., " ." ".
."
''''
. .2
."
" ...
"98'
47 .17"
'0'"
""" """ """ ",..
4604 " 4456"
29 \1 "
4167
3880
"00
SO 20
NA NA NA NA NA NA NA NA NA NA
'70' NA
20 SO 2230
2220
NA NA
'" '"
NA NA
"2
NA NA NA NA
'"55 ' "
... NA NA NA NA NA NA NA NA NA NA NA NA
NA NA
NA
Boo"
Boo" Boo" Boo" Boo"
BIO'S
6 ic'S BIO'S
Boo'~
BOO'·
Boo'·
600' 3
HPLC ,2
HPLC' ~
HPLC ' 2
Est,mated value calculaled Irom mean dala Aiter lood versus lUling Re/arences; 1 Tartaglione et al (1986); 2 W ingen
a b
,so
,
1.11 7q12h '00 13q12h '06
""
0.71
", '00
2)0;250
500 500
099
500
12(M) 200 S(M)/S(F) 250 S(M)/S(F) 500 12(M) 2SO 250 12(M) 12(M) 2SO 12( M) 500 12(M) 500 12(M) 500 12(M) ,SO 12(M) ,SO 12(M)
18(M) 18(M)
18(M)
-
••
~
,"2
0
~
a
~
Cl
~
0
~
~
,,
""3 •8
~
~
~
,~
Clill. Pl!armacokilln. 19 (6) 1990
444
should not cause a clinically significant absorption problem and may in fact be helpful in minimising gastric distress (reviewed by leBel 1988). As the dose ofciproflox3cin administered orally is increased, Im ax appeaf5 to increase also (Hoflken el al. (98Sh; Plaisance el 31. \987; Tanaglione et al. 1986). Although the presence ora saturable process involved in the oral absorption of ciprofloxaein might explain these results, Plaisance et 31. (1987) have suggested that a more likely explanation is the potential variability in disintegration/ d issolution rates between the various dosage forms and the method of administration . Homer el a!. ( 1984) and others have reported that increasing oral doses of cjprofloxacin cause a proportional increase in e max (Bergan et a!. 1988). In direct contrast, Bomer et al. (19868) and Hoffken et al. ( 1985b) have reponed no nlinearity between serum concentrations and oral doses of ciprofloxacin > 25Omg. Differences in assay methods used to quantify serum ciprofloxacin concentrations, small heterogeneous sample sizes and differe nces in protocol design probably explain, at least in pan, the varying res ults reponed between these studies. A linear relationship between serum concentration and intravenous dose has been reponed by several investigators for doses of ciprofloxacin up to 250mg (Bomer et al. 19868; Drusano et al. 1986a; Dudley et al. 1987; Ljungberg & NilssonEhle 1988). The reported absolute bioavailability of ciprofloxacin is approximately 70%, with the mean ranging from 56 to 77% (Davis et al. 1987; Drosano et al. 1986b; HofIken et al. 1985b; Wingender et al. 1984; Wise et al. 1984). Among healthy volunteers Drusano et al. (l986b) have reponed the absorption to be reliable, with coeffici ents of variation of bioavailability of approximately 10%. Davis et al. (198 5) have demonstrated a significant difference in the bioavailability of different dosage forms of ciprofloxacin. The 250mg tablet is less bioavailable than either the 500mg tablet or a s0lution formulation (74.1% for the 250mg tablet versus 78.7% for the solution and 500mg tablet). The differences in bioavailability between these
products, although statistically significant, are probably not clinically relevant. 2.3 Distribution As with other new fluoroquinolones, the protein binding associated with ciprofloxacin is relatively low at approximately 30% (Dudley 1987; Hofl"ken et al. 1986). The degree of binding does not appear to be significantly affected by pH or concentration (J OO5 et al. 198 5). As can be concluded from the pharmacokinetic studies summarised in tables II and III, the volume of distribution of ciprofloxacin al steady-st8te (V u) is large, with a reponed range after oral or intravenous dosinB from 1.74 to 5.0 Lfk&. Phannacokinetic modellinB of serum ciprofloxacin concentration data over time after oral dosinB appears to be best fitted by a2
(mgl
50 100 200 100 200 200 200
(Nxl
6(M)f6(F) 6(MI/6(F) 5( MI/5(F) 6(M) 6( MI 6(MJ 12(M) 12(M) 12( M) 12(M) 12(M) 121M) 121M) 121M) 121M) 121M) 9(M) 9( MI 9( M) 9(M) 9(M) 9(M) 6(M) 6(M) 81M) 81M) 81M) 81M) 6(Ml/6(F) 6(MI/6(F)
.....
-'
-,
-'
7q l 2h 13q 12h
7ql2h Ilq l 2h
7ql2h Ilql2h
-'
tW. o l
NA 2.28 3.80 NA
6 .48 O.SIt> 0 .47t> 0 .53t> 1 .04t> !.1It>
1.56t> 1.51)1> I .SSt> 1.6 a 2. l a 3.1<1 .... 2.0
32 NA NA 6.3 NA NA NA 1.23 2.80
'" 30 30 __
10 10 10 10 10 10 10 10 10 10 30 30 30 30 30
'" , NA 10 3 3 , 15 15
1.1J9I>
NA NA
15 15
(minI
Leoglh 01 C"",. inlU$lon (mg/L)
3.0
1.2
1.74 2.42 2.58 2.53 3.40 5.14 7.70 2.24 3.36 S.17 2 .41 2.81 5.97 ....5 2.90 8.11
I.s..
1.23 2.68 5.31 3.9-4 7.22 5.&4 NA 0.70 0.71 0.71 1.53
mg/L ' h)
AUC
NA NA NA I 74 190 1.80 NA 2.29 219 2.10 I 75 202 1 77 188 1 90 1.86 195 1.97 197 2. 17 2.40 200 198 225 NA 3 .72 394 3.30 NA NA
(L{kg)
Vss
01 ciprofioxaCln alter Intravenous administration
..
'"
'66
NA NA NA
'"
NA NA NA NA NA
'07
'"'<5
235
'"
2.31 2.27
'"
,..
'00 '00
293
,
NA NA NA
'" '60
3"
tL/kg)
v,
46.38
"32 56.76
""
4.27
333 373 3.45 300 306
55.02
"'''
<329 3<.02
' .0
31 .32 29.10 31.68 30.12 30.72 30. 12 29.82 26.68 46.94 46.00 39.85
32.66
28.50 37.32 36.60 36.18
29.66
""
36.00 39.12 24.60 25.20
(LJh)
Cl
3.65
4.22
' 62
3.44 3.67 3.60 ' .00 4.21
H9
3.91 3.55 3.18
33<
3.55
3'"
3.51
.'"
3.'
NA NA NA NA NA NA NA NA NA NA NA NA NA NA NA NA NA NA NA NA NA NA NA NA
' .3
..
' .32 ' .36
3.62 3.66 3.53
'-1"1
NA NA NA 2.24
(LJkg)
v,
" .60
4410
2790
25.80 25.20 23.52 18.8418.7S18 4Z22.54 21 .52 18.56 19.89 28.74 NA 24.48 25.56
"'.53
17.82 16.92 21.60 19.32 20.28 22.20 22.92
"'"
2316 18.90 2142 IS 12
Cl, IL/h)
'" " "
75.7 NA NA NA NA 62 62
.. 0
...
.'" ,
NA NA NA NA NA NA NA NA NA NA NA NA
"
60
53'
,,.
'.
1%1
... " ..."
HPLC' HPlC' HPLC' HPlC'
...'
HPLCS HPLCO
HPLC~
HPLC~
.~.
Blo·
.~.
.~.
.~.
.~.
.~.
.~.
.... .... .... ....
HPLC' HPLC' HPLC' HPLC2 HPLC2 HPlC2 HPlC3
Assay
d Value de
25 50 50 50 75 75 75 100 150 200 100 150 200 100 lOll 200 50 100 250 100 200
25 25
Dose
~rmacoklnellcs
NO.
r.bIe III.
-
~
~ ~
,
I
D
o
ii
~
l
~
• 3
~
g
,Cl
l(M)f9(F) 5(M)/ 5(F)
B'.
(vitreous )
CSF (inflamed) (noninttamed) Eye (aql.l9OUs humour) (anterior chamber)
Brorw;:hial (biopsy tissue) (secretion s) Cervix
Blister lIuid
~MI
3
• 10
3
16(M)f7(F) II (M)/ 3(F} 25 '
"
21
" n
5(M)J1(F} 6(M)/6(F)
,
",,.
7(M)/5(F}
12
"
Ascites
(sa_)
No.
400(1) 600(11 200(3) 400(1]
7~3)
200(2qI2h) 750111 75012)
500[I3q8h) 500[8q12h) 500(1) 300(1) 300{l)n 200(3q12h]
200(11 500[4ql2h) 200(1 1 400(1] 500(11
75011) 500(11
200 25011)
tOO(1)
''''91 [Irequency)
DoH
IV
""
IV
IV
IV
""
""""
IV
po, Iv<'
IV
PO
""
IV
Route
1.49
0.38
0 .74 0.42 2.26 3.51 1-9.2 2.27 0.6-1 .3 1.44 1.12
12.6 0.47 1.15 1.87 1.2-17.3 0.44 2.42 1.92
056
0.29
\.1·3.51 I .6-5.3i \.9-5.41 0.9-3.81 1.7-6 ..tl 0.7-1.81 0.9 -3.81
0.3
0.0<
8.02
0.27 0.21 0.09·0.26 0.22.(l.84 0.4 1·0.95 0.28-0.59 0.26-1 .1 0.16-0.29
1.05
7.' 10.3 7 .' 10.3 5 .69 8 .1\
0.9
10.0
0 0. 3 N' N' N' N' 0."
0.74 0.15 0 .8 9
7.' 1.1
6.03
68·225
•, 1- 1.5
I .'
,•
2· 2.5
0.'"
N'
0.37 0.23 0.16
N'
0.571 1.61 g 0.19
1-1.5 1-2.5 1·2 1.5 · 2 1-2.5 1-\.5 1-2.5 1.5·2 1-2.5
I ·'
1.5-2
HPLC
2
HPLC
B.
Bk>
15
"
"
12
"
10
7
8 9 HPlC
,
,
3
•
,
Relerence
50
HPlC
50
HPLC
50
HPLC
B.
HPlC
B.
50
8.
Assay
2 1.5-2
NA
0.'
I .$-2
I
2
2 1-1.5
NA
1.5·4
I .$-4 I .$-4 I .. ..
8.9' 10.5 7 .7 7 .7 17 1.12
N' N'
NA
"
2
"
",
3 3
Hrum
1·2 1·2
12-24 1·2 12-24 2
I ·'
"'
3
tissue
Sampling tIme (h)
' .Il"
7.7 c 9.5 C
30
11-2
7.3
10
"
0.93
0.92
1.28
1.18
0.' 0.0
"'
serum b
c,: C.
0.8 ' .0
tissue"
Concentration
01 ciprollo_.cin aftar oral or intravenous administration
8
penelra~
Abdominal walilat
Body nuid{1issue
T.bIe IV . Tissue
;g
:0
~
~
-
,
I,
:.•
9,
~
••
500!1] 10011J 300(1] 300(1]"
9 5 22 19
Semen SemInal tluld SkIn
(1JS$I.I81
Pleural exuoale ProstatIC (ttuld)
Pe,.,oneum
Pe';'onea"'uld
6
Perlrenallat
7 '5 '0 25 10 10 5
5 15(MI/ 15/ F) 8 18 18 7 4 8
5(M)
Pancreatic juICe
Ovary
500\1 J 100(11 200{IJ
100[1] '0011) lOO(lJ 200\IJ 200\IJ 500!IJ 500!3qI2h1 500!11 500(3q12hl 100(11 750(1) 500[2qI2h) '00(1) 500(IJ !)OO(I) 100(')
500(1)
500(1]
200111
lOOp 1
5 16 S(M)/l(FJ 8 18
40011]
750(1]
Kidney Lung tissue Lymph Muscle
I{MJ/9(F)
21
Hepatic tissue
300{1]h 750( 1)
IV PO PO IV
IV PO
IV PO
IV IV IV
PO
PO
PO IV tV
IV IV PO IV
IV"
PO
PO
IV
34 133
017
NA
017 0.32 06-'3
0.6-418 3.03 3.0 0.7 , 023
08-46 116 1.2 02 02 032
DIS 0.32 1.1 2 0.15 08 16 2 1.0 7 ' 1 0,02-57 0.27·248 104·24 168·256 NA NA
0.11
NA
0.2 1.17 31 1.89
0015·45 059·094 227 214 296 094 303 21 35 5 072
0 .. 7 06 N...
065
6 18
076
I 18 366 NA
21 12 NA NA
NA
1..-12
NA
NA
NA
6 .03
603
0.6-1 3
06-13
0.6-1 .3
06·1 .3
4.25 0.32 2.29 110 0.59 042 0.5 08 192
2.7-37.8
12.76
5.94
1.98
2.604
1.82
1.37
1 7·S 4
0.13 tV
16·2.5
O.36-{).39
400(3) 600(1] 300(1) 300(1]" 300(1)
1 6·26
0.33-0.55
400\21
Intestinalmucul
1{M)/9(F)
19
22
19
22
Gallbladder lissue
Fundusmyomelrium
Fallopian tube
j
2
1-3 23-9 1-2 033 12 12 2-3
2-44
, 2·37
2,3 05
12
12
12 2·3 , · ,5
2-3 1 6
' -3 23 -9 ' -2 033 12 '2 2-3
2-44
1 2·37
2·3 05
12
12
12 2·3 15-2
2·3 1 6
08·38
NA
NA
15·2
15·2
' ·2
Boo Boo Boo Boo Boo Boo
HPLC 810
Boo Boo
B>o
Boo
e.o
B,o HPLC HPLC Boo
6'0
6'0
8'0
610
Boo
FOI footllOl'$ and f.f'f'n("M.
08·38
NA
NA
1· 15
1-15
1-2
l S - 2 ' 5·2
$" P •• 8
23 24 25 26 26 17
18 22
17 21
19
20
19 17 12
17 18 8
16
3
3
12
12
••
~
:)
~
:;
g,
;::;
"§.
~ 0
;;:
~
;::
3
-
g
5
~
'"
Range.
FIve patients per sampling
lime.
tv dose preceded by SOOmg twice dally lor 3 days.
c.....•.
PO 0.'
NA 1.28
NA
0.32 1.28 0.2-0.6
0.17
NA
2.27 2 .• 8
-"" O.
0.63
1.5
,
NA
1 . ..
" 153
,
2~
12
•
2
1
•
2
,
1.5-. NA
,
12 2·'
NA
NA
NA
1
grum
tissue
Sampling time (h)
0.33 0.66
NA
0.58 0.63
Ct:Cs
""
""
""
HPLC
""
Assay
2
2 30
19 17
29
28
27
Reference
k
IV dose preceded by 2 doses 01 750mg with a 12-hour in18fVI" I Ratio 01 sputUm to $6fUIT1 AUC. Referenca: 1 Silverman 8\ II. (1986): 2 Esposito a t II. (1987): 3 Dan at II. (1987);" Brogard al aI. (1985): 5 Jenl el at (1987): 6 Parry e1 at (1988): 7 Tanimura e1 a t (1988); 8 6efga n e1 at (1988): 9 LaBel at at (1988): 10 Hooeyboume at a t (1987): 11 8&fgogne-Beruin e l al. (1988); 12 Ge~11I&r at ai , (1988): 13 WoIlI at al. (1987): ,. Skoutalis at al. (1988): 15 Joos at at (1988); 16 Brismar al al. (1990): 17 Oa!lChner al al. (1986): 18 Hopi at at (1988): 19 Oaltloll & EickabBrg (1985): 20 Pederzoli e1 al. (1987): 2 1 Lockley al al. (1986); 22 Boerama at ai , (1985): 23 Oan at al. (1988): 2. Grabe at al. (1986): 25 Hoogkamp-Korstanje II II. (198.t): 26 Daltloll & Weidner (198.t): 27 Fraschlni It al. (198T); 28 Hoogka m p-Korstanje It ai , (1988); 29 DaviS It al. (1981): 30 false. e1 ai , (1988) , AbbreviatlQtU; Ct • drug ooncenlratlon in tissue: C • • drug ooncentratlon in 5efUm: for other abbreviations, SBB lable II.
It
SO· 150%.
200mg IV [I ] .fler last or,l dose. Patients with Indwening biliary drainage lubeS. Value equals blister fluid C"",.Jserum Cma •.
d e I
o
Ratio 01 bile OOOC8f1tration 2 hours altsr dose to
c
250(1)
po, Iv<'
O.~.88
1V
200\1(
SOO[6q12h]
2.'
PO
250( 1]
Mean value or rInge, given in mg/l Of g/llg. Mean value or range. given in mg/L
4(MI/4(F)
"
10
0.21
1V
0.51 0.39
1 02
'"
1.31
0. 16
NA
1.55
1.31
tissue-
Concentration
0.058
1V
PO
ROUIe
PO
SOO{ 1( 100( 1]
200\1)
SOO(1 ) SOO(l3q12h] 500(q l 2hJ 750(11
[freqvency]
(mg)
"'"
a b
Turbinate booes
4(M)/6(F)
Tonsils
"
5 4(MI/4(F}
6 9 7
21(M)/ I 5(F}
32\M(
•
(cystic fibrosis)
No.
(sex)
Subcutaneous fat
S""",m
Body fluld/1lssue
nbllo tv. (com.)
~
e
:0
~
[
a?i'
~ ~ ~
Omu:al PharmacokmtlHts of Cipronoxacm
(Boerema et at. 1984. 1985; Honeybourne et al. 1987; Hopf et at. 1988). Ciprofloxacin achieves cerebrospinal fluid (CSF) concentrations that are equal to or higher than the MIC or MBC of most Enterobacteriaceae that cause acute bacterial meningitis (Wolff et a1. 1987). CSF penetratIOn associated with noninflamed meninges occurs, but to a lesser extent than is observed with inflammation. The ratio of achievable CSF ciprofl oxacin concentrations to MBC for staphylococcal. streptococcal or pseudomonal organisms is probably insufficient for reliable treatment of meningitis. AI present the utility of treating bacterial CSF infections with ciprofioxacin is questionable, pending further Investigation. Ciprolloxacin concentrations found in the antenor chamber and vitreous of the eye afler single and multiple doses exceed the MIC for most Gramposiu ve and Gram-negative bacteria that usually cause ophthalmic infections. This findi ng suggests that ciprofi oxacin may be an effective agen t for prophylactic use in ophthalmological surgery and for the treatment of intraocular infections due to susceptible organisms (Joos et al. 1986; Skoutelis et aJ. 1988). Similarly. the penetration of ciprofloxacin IOto tonsil tissue and turbinate bones is sufficient to suggest clinical success in the treatment of bacterial rhinopharyngeal infections (Esposito et al. 1987; Falser et al. 1988). Ciprofioxacin is concentrated in bronchial mucosa tissue as evidenced by lung tissue/ serum concurrent drug ratios that have been reported to exceed 1.5 (Honeyboume et aJ. 1987; Hopf et a\. 1988). Penetration into sputum and pleural exudate is also significant and appears to exceed the MIC of most respiratory pathogens for up to 12 hours after a dose, depending on the size (Bergagne-Bertzin et a!. 1986; Hoogkamp-Korstanje & Klein 1986; Hopf et al. 1988). This extensive penetration into respiratory-associated tissues and fluid s probably explains why some cli nical trials of ciprofloxacin in chest infections have demonstrated effi cacy for pneumococcal and other Grampositive infections despite the fact that MIC sensitivity data paired with achievable serum concen-
449
tTation data suggest otherwise (Honeyboume et al. 1987; Hoogkamp- Korstanje & Klein 1986). Therapeutic concentrations of ciprofloxacin are achieved in liver tissue. gallbladder tissue, pancreatic fluid and bile after single o r multiple doses of ciprofioxaclO (Brogard et al. 1985a; Dan et al. 1987; Pederzoli et al. 1987). Among these ussues. clprofloxaclO achieves the highest ratio versus simultaneous serum concentration in bile. Biliary concentratio ns of the drug 10 times that in serum have been reponed (Tanimura et al. 1986) and in addition to unchanged ciprofloxacin, at least 3 dif· ferent biologically active metabolites ha ve been isolated. The presence of these active metabolites. as discussed above, isthought to be the reason that microbiological bioassays of biliary ciprofloxacin concentrations are approximately 40% greater than those found with HPLC (Brogard et al. 1985a; Tanimura et al. 1986). Because the MIC values of each metabolite considered together with the proponion of each metabolite in bile do not full y account for a 40% difference, Tanimura et al. (1986) have suggested that ot her ciprofi oxacin metabolites in addition to those already identified may be excreted in to the bile. The clinical significance of this is at present unclear. Ciprofloxacin concentrations achievable in peritoneal or ascitic fluid are sufficient to inhibit the growth of most aerobic bacteria that usually cause infectious peritoneal diseases. whether the conse· quence of abdominal surgery. peritoneal dial ysis or intra-abdominal catheter placement (Lockley et a1. 1986; Silverman et al. 1986). Following an intravenous dose of ciprofloxacin 2ooms. therapeutic concentrations have been reponed in abdominal wall fat , muscle and peritoneal tissue for up to 2.5 hours. These data suggest that ciprofioxacin may be suitable for colorectal surgical antimicrobial prophylaxis when given 35 a single intravenous dose immediately preoperatively (Brismar et al. 1990; Silvennan et al. 1986). In gynaecological tissue, including fallopian tubes, uterus, ovary, cervix and fundus, ciprofloxacin concentrations have been reponed to exceed corresponding serum concentrations 1.3- to 3.7·fold. These data indicate that ciprofioxacin should be
elm. PhorIllQ,oklll('l. 19 (6) / 990
4SO
very useful for the treatment of many gynaerological infectious processes (Gerstner et al. 1988). After oral administration. d pfofloxacin concentrales in prostatic tissue and seminal fluid to ap-
proximately 2 and 10 times the corresponding serum concentration. respectively. It may, therefort. prove to be an extremely effective drug for
the treatment of prostatitis and urinary tract infections (Bocrema el al. 1984, 1985; Dalhoff & Weidner 1984; Grabe el al. 1986). 2.4 Metabolism
From tables II and III il is obvious that. for ciproflo xacin. non renal clearance mechanisms are important. accounting for approximately one-third
of its elimination. Four metabolites, termed MI, M2. M3 and M4 (fig. I), have been isolated from urine and their respective molecular structures have been determined by nuclear magnetic resonance and mass spectromClry techniques (Gau et al. 1986). Studies using radiolabclled ciprofloxacin have demonstrated that in addition to the urinary elimination of unchanged drug. the M I, M2, and M3 metabolites are excreted into the bile and consequently into the faeces (Beermann et al. 1986). M3 (oxo-<:iprofloxacin) is the major urinary metabolite accounting for approximately 6% ofa 200mg intravenous dose or 250mg oral dose of ciprofloxacin. M2 (sulfo-<:iprofloxacin) has been identified as the primary faecal metabolite, with approximately 6% of an oral dose and 1.3% of an intravenous dose rccovered in the faeces. Hoflken ct al. ( 1985b) reported that the proportion of the relative amount ofciprofloxacin metabolites to the total amount of drug excreted in the urine increased from 29.7% after intravenous administration to 42.7% after oral dosing. indicating a probable first-pass effect of the liver. The M2 metabolite appears to be the preferentially fonned first-pass metabolite, since the amount excreted after intravenous dosing is significantly less than that after oral administration, 4 vers us 9.6%, respt(:tively (Drusano 1987). Oinically, howevCT, the overall significance of this first-pass effect (ap-
proximately 5%) is thought to be unimportant (Borner et al. 1986b; Beermann et al. 1986). Faecal recovery of ciprofloxacin accounts for about 15% of the dose following intravenous administration and may be the result of elimination direttly through the intestinal mucosa (Wise & Donovan 1987). This, coupled with biliary excretion of the unchanged drug and its metabolites. implies that hepatic extraction and excretion into the bowel is a significan t nonrenal pathway for ciprofloxacin clearance. Biliary excretion may, however, be a minor elimination route since only 0.3% of the drug is excreted unchanged in Ihe urine over 24 hours (Brogard et a!. I 985a). 2.5 Excretion In addition to Ihe elimination of ciprofloxacin through a combination of metabolic degradation, biliary excretion and possible transluminal secretion across the enteric mucosa which have already been discussed, other important routes include glomerular filtration and tubular secretion. Renal clearance mechanisms aceount for approximately two-thirds of the total serum clearance of ciprofloxacin (Drusano 1987). Most investigators have reported the t.,., of ciprofloxacin to be in the range of 3 to 4h (tables II and Ill). On the basis of this half-life a dosing interval range of 8 to 12 hours has been recommended for most moderate to severe infections, and an interval of 12 to 24 hours for mild or non-lifethreatening infections (Drusano et al. 1986a,b; Gonzalez et al. 1985a,b; Tartaglione et a1. 1986). Tartaglione et al. (1986) and Plaisance et al. (1987) have reported a substantially longer I.,., but a proportional AUe for oral doses of ciprofloxacin 750mg or greater compared with doses of 200 10 500mg. Apparent total clearance and renal clearance of the different dosing regimens were generally comparable, although a trend towards decreased renal clearance associated with the larger doses was reported by these workers and others (Hoflken et aJ. 1985b; Homer et al. 1984). Possible explanations for the increased t.,., suggested by these different investigators include nonlinear ciproflox-
45'
Clinical Pharmacoklnctlcs of Ciproflo~acln
acin elimination at higher dosage levels and an absorption phase that is a slow pH-dependent continuous process. Other investigalors, from studies with intravenously administered drug, have also suggested that the elimination may be nonlinear. especially with larger doses of the drug (e.g. > 200mg) [Drusano et al. 1986a). To dale, however. no evidence unequivocally substantiating nonlineari ty has been rcported. The rcnal dearance of ciprofioxacin has been demonstrated to be far in excess of crealmine clearance. suggesting that lubular secretion must be occurring (Dudley et a1. 1987; Gonzalez et a1. 1985a.b: Pla isance el al. 1987; Tartaglione el a1. 1986: Wise CI a1. 1984). The fae! that probenecid has been reported to reduce the renal excretion of ciprofioxacin by 50% confirms this hypolhesis (Wingender el al. I 985a). SalUration of tubular secretion processes has been suggested as the mechanism by which renal clearance tends to decrease as the dose of ciprofioxacin is increased (Dudley et al. 1987; Tartaglione et al. 1986). Ciprofioxacin docs nOI ap.pear to undergo significant flow-dependent tubular resorption. as the correlation between urine flow rate and renal clearance is poor (r = 0.0008: p = 0.63) [Davis et al. 19851. 2.6 Multiple Dose Studies Multiple dose studies of ciprofloxacin pharmacokinetics have yielded contradictory results. dependmg on whether the drug was administered orally or parenterally. Several investigalOrs have reported drug accumulation in conjunction with oral multiple dosing regimens (Brumfitt et at 1984; Gonzalez et al. 1984; leBel et al. 1986). These studies reponed substantial differences for t'h values and IOtal systemic clearance values between single and multiple dose administration (Amoff et al. 1984; Brumfitt et al. 1984; leBel et al. 1986). leBel et al. (1986c) and others have postulated that a saturable nonrenal clearance mechanism that is more active for the first dose than for subsequent doses is responsible for this type of pharmacokinetic behaviour (Drusano et al. 1986a; Dudley et al. 1987; Gonzalez el al. 1985b). Other investiga-
tors. howcver. have reported Ihal after multiple oral doses of ciprofioxacin no significant accumulation was detected. and further thai no signi fi can t differences in 1<" or systemic clearance were observed between the fi rst and the last multiple oral dose (Bergan el al. I 986b). Nor have significant differences been reponed from studies of multiple intravenous doses. and the investigators have not reponed significan t accumulation (Gonzalez et al. 1985a; Forrest et al. 1985). Drusano et al. (1986a) in a dose-ranging study incorporating a constant infusion arm have reported that differences ap.proaching statistical significance were seen in mean serum ciprofiOllacin clearance. suggesting that future multiple dose intravenous studies incorporating larger ciprofioxaci n doses (> 200mg) may reveal dose-dcpendcnt nonlinearity in pharmacokinctics. The widely differing pharmacokinetic data reported from both oral and intravenous multiple dose studies are probably the result of differences in protocol design. numbers of patients studied. assay technique and difficulties in determining when Ihe absorption phase has ended in oral studies. Additional. carefully controlled cl inical trials are necessary to elucidate the impact of multiple dosing on ciprofioxaci n pharmacokinetics. 2.7 Special Population Pharmacokinetics The pharmacokinetic disposition of ciprofioxacin in the elderly population is s ignificantly different from that in the young. In conjunction with studies of single dose oral ciprofiollacin. several investigators have reponed that the renal clearance of the drug is significantly less than that observed in the young, that the AUC and Cma~ are signi ficantly higher and that the t'n is longer (Ball el al. 1986; Bayer et al. 1987: Guay et al. 1988; Ljungberg & Nilsson-Ehle 1989: leBel et al. I 986a). Significantly lower systemic clearances, non renal clearances and Vu after single oral eiprofi oxacin doses have also been reported in the elderly (leBel et al. 1986a). Data from single dose intravenous ciprofloxacin administration studies in the elderly are very similar to those reported after oral administration (Naber et a1. 1989). Multiple oral dose
45' studies, comparing pharmacokinetic data after the last dose to data compiled after the first dose, have reported that the AVe and 1'1:1 are increased and that renal and system ic clearances are decreased. These data taken together suggest that the phar. macokinetics of cipronoxacin in the elderly population are significantly different from those observed in the young. The prolonged I'll of ciprofloxacin and the increased AUe observed in the elderly can lead to higher first dose and steady-state serum concentrations than in younger subjects. As a result, any con-
centration-related side effects of ciprofloxacin would be expected to occur more frequently in elderly patients receiving dosage regimens recommended on the basis of data from younger adults, ailhaugh none have been identified to date. To prevent accumulation and potential associated tOlticity, several clinicians have suggested that it is appropriate to avoid dosage intervals shorter than 12 hours; generally, however, the dose and dosing interval compared with the younger population need not be altered (Bayer et al. 1987; Dudley 1987; Guay et al. 1988; leBel & Bergeron 1987; Naber et al. 1989). Acute illness does not appear to alter the pharmacokinetics of ciprofloltaci n in the elderly, and therefore dosage alterations because of the presence of acute illness in these patients do not appear to be warranted (Guay et al. 1987, 1988). It is well recognised that patients with cystic fibrosis have enhanced clearance or altered absorption of certain drugs compared with healthy volunteers (Kelly & Lovato 1984). Almost all pharmacokinetic studies of ciprofloltacin in patients with cystic fibrosis have concluded that the disposition of the drug does not differ significantly from that in healthy control populations (Bender et al. I986a; Davis et al. 1987; Goldfarb et al. 1986; Stutman et al. 1987). This is in contrast to data derived from pharmacokinelic studies with ,B-Iactams (Jusko et al. 1975) and am inog,lycosides (Levy et al. 1984), where antibiotic pharmacokinetics have been reported to be significantly different requiring alteration of dosing strategy in patients with cystic fibrosis. For these reasons, ciprofloxacin represents a major advance in the treatment of bronchopul-
Cfil1. Pharmacokinel. 19 (6) /990
monary infections in patients with cystic fibrosis. leBel et al. (1986b), in contrast to other studies of the pharmacokinetics of ciprofloxacin in cystic fibrosis patients, have reported significantly shorter half-lives and smaller V$S compared with controls. The reason for the discrepancies between this study and other work previously cited is not clear. These pharmacokinetic data suggest that ciprofloxacin dosing regimen alterations are probably not required in patients with cystic fibrosis. Numerous pharmacoldnetic studies of the disposition ofciprofloxacin in renal failure have demonstrated significant differences between healthy volunteers and patients in renal failure. As a result of the presence of nonrenal routes of elimination of ciprofloxacin, the serum clearance in anephric patients is approximately half that of healthy controls (Drusano et al. 1987a). The t.,., of ciprofloxacin in patients with end·stage renal disease (creatinine clearance < 10 mljmin) has been reported to be approximately twice that of healthy controls (approximately 8 hours) [8oelaert et al. 1985; Danielson et al. 1985; Drusano et al. 1987a; Kowalsky et al. 1985; Singlas et al. 1987). Forrest et al. (1988) also reported an apparent increase in the elimination half-life (although not significant) in patients with renal failure, but more importantly noted that in palients with severe fai lure, the variability in I'll was very large compared with that seen in healthy controls. The observed AUe is also significantly increased in patients with renal failure and max concentrations may be higher in these patients (Boelaert et al. 1985 ; Danielson et al. 1985; FOTTest et al. 1988; Gasser et al. 1987; Kowalsky et al. 1985; Singlas et al. 1987). On the basis of these data, and particularly on the variability in t.,., as reported by Drusano et al. (l987a), among patients with severe renal failure, it seems appropriate to recommend that changes in the ciprofloxacin dose (as opposed to the dosing interval) be made in order to achieve concentrations of ciproflolacin that are similar to those observed in patients with normal renal function. In patients with renal dysfunction (creatinine clearance less than 20 to 30 ml/ min/ 1.73m 2) the daily dose reduction should be limited to a maximum of 50% and. because tbe variation in half-
e
Clinical PhaTmacoklnelic-s ofCiprofloudn
lives is large. the maximum dosing inlerval for such patients with serious infections should be 12 hours (Boelaert e\ al. 1985: Forres\ e\ al. 1988: Gasser et al. 1987). This approach should maintain ciprofloxacin concentrations within the therapeutic range for most of the dosing inteTval. The haemodialysis extraction ratio of ciprofloxacin has been reported to be approximately 30%. with no more than 2% of the dose removed by dialysis over a 4-hour period (Boelaert el al. 1985: Singlas et al. 1987). Therefore. due to this rather minimal impact of a 4-hour haemodialysis period on ciprofloxacin disposition. dosage supplementation after haemodialysis is not recommended. Similarly. in a study by Shalit et al. (1986), the fraction of the ciprofl oxacin dose removed via Ihe peritoneal fluid pathway in patients undergoing
chronic ambulatory peritoneal dialysis (CAPO) was reported to be approximately t%, implying that the overall pharmacokinetic disposition of the drug is lillie affected by CAPO. Further. these same investigators and others have demonstrated that therapeutic concentrations against bacterial pathogens commonly associated with peritonitis in CAPO pat ients are rapidly achievable in Ihe peritoneal fluid afler oral doses of ciprofloxacin 750mg (Kowalsky et al. 1985). Although the clinical significance of liver dysfunction on ciprofloxacin pharmacokinetics has not been established. it would appear [as Bergan et al. (1988) pointed out in a recent review] that the effeet on ciprofloxacin elimi nation would be minima] since its biliary excretion is <1% of the administered dose and metabolism accounts for only about 15% of its elimination (Beermann et al. 1986: Brogard et al. 1985b,c). Studies of ciprofloxacin disposition in ci rrhotic palients have reported only small, cl inically nonsignifi canl alterations in the pharmacokinetics of ciprofloxacin compared with healthy volunteers (Drusano et al. 1987b; Lettieri et al. 1987). Formation of the oxo-metaboli te ( M3) was reduced by 50% in cirrhotics. whi le M 1and M2 concentrations were slightly increased. These data suggest that ciprofloxacin dosage adjustments are not necessary in patients with cirrhosis.
3. Drug Interactions and
A d~erse
Effects
3.1 Drug-Drug Interactions Drug-drug inleractions can be divided into those originating from pharmacokinetic mechanisms and those originating from pharmacodynamic mechanisms. Pharmacokinetic inleractions are due to altered drug absorption. distribution, metabolism. and elimination. Pharmacodynamic interactions occur when a drug affects the actions of another drug. The fluoroquinolones exh ibit drug-drug interactions of both types. The concomitan t oral administration of magnesium- and aluminium-containing antacids has been reported to result in a 6- to IO-fold decrease in the absorption of the fluoroquinolones, including ciprofloxacin (Fleming et al. 1986: Flor et al. 1988: Grasela et al. 1989: Hoflken ct al. 1985a: Maesen el al. 1987: Nix et al. 1990; Prcheim el al. 1986). Even whcn doses of the 2 agents were separatcd by 2 hours or more. a substantial rcduction in fluoroquinolone absorption persisted. In contrast, oral coadministration of calcium-containing antacids has been reponed both not to significantly afTect fluoroqu inolone absorption (Fleming et al. 1986; Flor el al. 1988) and to significantly reduce it (Sahai et al. 1989). Recent studies have documcntcd substantial reductions in the bioavailability of ciprofloxacin and norfloxacin when these agcnts are coadministered with the antiulcer drug sucralfate (Nix et al. 1989b: Parpia et al. 1989). Of note is the fac i that this interaction persisted even when administralion of the agents was spaced 2 or more hours apan. A mechanistic hypothesis is thaI the rcd uction in fluo roquinolone absorption is due to the formation of insoluble and hence unabsorbable drug-cation chelates in the gastrointestinal tract. Histamine H2-reeeptor an tagonists. such as ranitidine and cimetidine, have been documcnted nol to alter fl uoroquinolone absorption (HofIken et al. 1986; Wingender et al. 1985b). Magnesium-, aluminium- or calcium-containing antacids or sueralfate should not be used when alternative non interacting antiulcer therapy such as H2-receplor antagonists can be used. If the need to coadminister these agents cannot be avoided, one
454
recommendation is to space their administration as far apart as possible. Recent work by Polk el al. (1989) has suggested that a similar chelation interaction may also occur between the flu oroquinolones and iron preparations a nd multivitamins with zinc. Patients receiving ciprofloxacin or other fluoroquinolones should be advised 10 avoid products containing iron and zinc. Agents that alter gastric motility, including pirenzepine, scopolamine and metoclopramide may affect the absorption of fluoroquinolones (HofTkcn et al. 1986: Wingender et al. 1985b). However, these drug-drug interactions are not clinically significant during therapy using multiple dose fluoroquino-
lone regimens. A number offluoroquinolones have been found to reduce the hepatic metabolism of coadminis. tered xanthines such as caffeine and theophylline (Beckmann et al. 1987; Bowles et al. 1988; Carbo et al. 1989; Davis et al. 1989: Gregoire et al. 1987; Harder et al. 1988; Healy e tal. 1989; Hoet al. 1988; Niki et at. 1987; Nix et at. 1987, 1989a; Raoof et al. 1987; Rogge et al. 1988, 1989; Sano et al. 1987; Schwam et al. 1988; Staib et al. 1987; Takagi et al. 1988; Thomson et al. 1987; Wijnands et a!. 1984, 1985, 1986. 1989). Ciprofloxacin reduce1the me· tabolism of the xanthines by approximately 15 to
-.
In the clinical situation, caution is advised when using any fluoroquinolone in combination with a xanthine compound such as theophylline; close monitoring of serum theophylline concentrations is recommended in any patient receiving these drugs. The clinical significance of inhibition of melabolism of other drugs remains unclear at present. Clinicians should generally be aware of the possibility of reduced drug metabolism resulting in adverse effects whenever the fiuoroquinolones are coadministered with drugs which depend on he-patic metabolism for their elimination. Case reports have documented quinolone-associated increases in the prothrombin time in patients receiving warfarin concurrently with ciprofloxacin, ofloxacin and norfloxacin (Loor & Matetzki 1988; Linville & Malanin 1989; Kamada
Cltn. Pharmacoktnl't. /9 (6) 199()
1990). Hence, patients who are receiving long term warfarin therapy and for whom a quinolone antibiotic has been prescribed should be monitored for changes in prothrombin time. Case reports have suggested that the fluore-quinolones may reduce the metabolism of cycle-sporin and hence potentiate the nephrotoxicity of this agent (Avent et al. 1988; Elston & Taylor 1988). Because formal pharmacokinetic studies have not. however, found a significant interaction between these: 2 agen ts. these: drugs may be used together with appropriate monitoring (Lang et al. 1989; Tan et al. 1989). The mechanism of these interactions is unclear. The inhibition of metabolism may be related to the 4-oxo metabolitcs of the fluoroquinolones but more reeent data suggest that the sequence N-.c ., NC·N.c (where N- >z nitrogen of the piperazine ring) is the entity responsible for metabolic inhibition (Harder et al. 1988). The metabolic inhibition appears to be dose-related, at least for enoxacin and ciprofloxacin (Harder et aJ. 1988; Rogge et al. 1988). l of The administration of probenecid, a bocker the anionic renal tubular secretory pathway. sui). stantially reduces the renal elimination of cipre-floxacin. refleeting competitive blockade of tubular secretion of the latter (Wingender et al. 1985a). There is thus the possibility that other drugs may interact with fluoroquinolones at this site to competitively impair their mutual renal elimination, thus elevating blood concentrations and perhaps enhancing therapeutic and/ or toxic effects. Urinary crystals of the fluoroquinolones have been noted in experimental animals subject t o high doses of these agents. Crystalluria in humans has been associated with haematuria (Garlando e t al. 1985; Wingender et al. 1985a) and is more pro~ lematic in senings of highly alkaline urine (due to reduced solubility of fluoroquinolones). Predictable interactions may involve concomitant therapy with bicarbonate or other urinary alkalinisers, patients with renal tubular acidosis or those with urinary tract infections caused by urease producing organisms such as the Proteus spp. Such interae-tions. however, have only rarely been reported to date.
Chnlcal l'harmacokmetlCs of Cipronoxacin
Fluoroquinolones have been demonstrated in animal models 10 inhibi t in I'i/,o the binding of the mhibitory neurotransmitter 'Y-am ino butyric acid (GABA) to its receptors in brain tissue (Hori et al. 1985. 1986. 1987: Scgev et al. 1988). In addition, Ihe NSAlDs nurbiprofen. indomethacin and fenbufen (nOI aV31lable in Ihe United States) have been shown /1/ I'/lrQ to potcntiale this effect on the nuoroquinolones. Thus. prcdicted interactions include an inCr("asc in thc epileptogenic potential of thcophylline. opiates. Iricyclic antidepressants. neurolcptics and other agents when coadminis(cred with nuoroquinolones. This interaction may be enhanced in patients also receiving NSAlDs for arthritis and other innammatory conditions. In Japan. reports of seizures in patients receiving the NSAID fenbufen in conjunction with enoxacin resulted in a warning to physicians (Morikawa et al. 1987). As Ihe clinical significance of this pharmacodynamic interaction between the nuoroquinolones and NSAIDs is unclear at this point, further studies in patients maintained on polypharmacy regimens are needed. 3.2 Adverse Reactions There have been several recent reviews of the adverse reactions probably or possibly attributable 10 the oral or intravenous administration of cipronoxacin (Arcieri et al. 1988. 1989; Ball 1986; Halkin 1988; Reiter et al. 1989: Sanders 1988: Schacht et al. 1989). Among the studies that used pooled worldwide data the reported incidence of adverse reactions to cipronoxacin is from 410 10% (Ball 1986: Halkin 1988: Schacht et al. 1989). This range compares favourably with the overall rates of adverse reactions reported for the nuoroquinolones in general. which is 4 to 8% (Halkin 1988). The incidence of adverse reactions to ciprofloxacin reported from studies done in the United States is approximately 15% (Arcieri et al. 1988, 1989; Ball 1986; Sanders 1988). In Europe and Japan the overall incidences of adverse reactions to ciprofloxacin have been reported to be 3% and approximately 6%. respectively (Ball 1986). A reason for the increased incidence of adverse reactions among
455
patients from the Un ited States is not clear. but it has been suggested to be the result of higher dosages of ciprofloxacin used in that country (Arcieri et al. 1986). Naber (1985) has reported a relationship between an increased incidence ofadvcrsc reactions and increasing doses of enoxacin. although no similar relationship wi th norfloxacin has been reponed (Holmes et al. 1985). A study by Schacht et al. (l989) in vestigating the safety of oral ciprofloxaci n as part of a worldwide clinical trial programme (9473 treatment courses) concluded Ihat Ihe vast majority of adverse reactions were mi ld to moderate (94%) and that the incidence of severe- reactions was 0.6%. Ciprofloxacin treatment was disco ntinucd due to side effects in 146 patients (1.5%). mostly as a result of gastrointestinal reactions (80 patients). The most common adverse reactions associated with ci pronoxacin involve either the gaSIrOinleStinal tract, metabolic and nutritional disorders. or disorders of the cen tral nervous system. These adverse reactions have been reported to be reversible after drug withdra wal and generally nOI dosedependent (Hal kin 1988). The gastrointestinal side effects consist of nausea primarily. d iarrhoea and vom iting. At least I case of pseudomembranous colitis has been reported in association with ciprofloxacin use (Schacht et al. 1989). Metabolic and nutritional disorders caused by ci profloxacin are primari ly those of asymptomatic increases in serum glutam ic oxoloacetic tr ansaminase or serum glutamic pyruvic transaminase. Elevated amylase. triglyceride. glutaminyl-transpeptidase. serum creatin ine and blood urea nitrogen values have been reported, although infrequently. as have isolated cases of acute renal failure and nephritis (Murray & Wilson 1990). The most com mon eNS-associated side effects include dizziness, headache and nervousness. Two reports of convulsions possibly caused by ciprofloxacin have been made. but are both complicated by past medical history of either alcoholism or epilepsy, and in both cases the seizures resolved promptly with no seq uelae (Schacht et a!. 1989). Reactions involving the skin have been reported and arc primarily either ras h or pruritus.
45.
Serious, life-threatening hypersensiti vity re actions have not been reponed. Adverse reactions attributable to other organ systems including thc haemalopoictic-Iymphalic. urogenital . special senses, cardiovascular. respiratory and musculoskeletal ha ve been reponed infrequently. ~Il the 4-quino lones. including ciproflox3cin, when administered chronically at high doses have been reported to cause severe cartilage erosions in Ihe weight-bearing joints of animals (Ingham et al. 1977; Schluter 1986; Tatsumi et al. 1977). Analogous effects in humans have not been reported. however. despite Ihe use of nalidixic acid and other quinolones for several years (Ball 1986). and children with cystic fibrosis have received various regimcns of high dose ciprofloxacin without apparent evidence of joint damage (Ball 1986). Pending additional clinical evidence clearly substantiating the safety of cipronoxacin in children. its use should be limited to those situations where an obviously favourable risk/benefit ratio can be documented. Other than local reactions at the site of intravenous infusion, the ype t and incidence of adverse events associated with intravenous cipronoxadn a re not substantially d ifferen t fro m those reported after oral adm inistration (Arcieri et al. 1989). Overall, these data suggest that ciprofloxacin is a relatively safe antimicrobial agent, and the incidence of adverse reactions attributable to cipronoxacin occur no more frequ ently than for comparative antimicrobials that have been widely used, including ootrimoxazole (trimethoprim + sulfamethoxazo!e), amoxicillin, ampici llin . the oral cephalosporins and cefotaxime (Schacht et aJ. 1989). Acktro wl~dg~m~nt
T he authors would like to g.ntefully acknowledge the tireless aid of Ms Dee Johnson in the preparatton of this
manuscript.
AOYlml H. FUJimlki F. SaIO K. Fujii T, Inoue M.el II. Oi nical ,sollte of Cmoboct,.,. !mmdii h'ihly miS\.Inl 10 new quill()o lones. Anlimicrobill ~nls and Chemotherapy )2: 922·924. 19&8 Att'ieri G. AUIIUSI R. Beckn- N. Doyk C, Griffilh E. elil. OinicaJ
e/lll. f¥,armacoklnn. 19 (6) 1990
eapenen.ce WIth ( ,proflouan ,n the USA. EUl'OpeIIn Journll ofOinoaol MlcmbiolOllY S: 220-22S. 1986 An:~ri OM. BeckeT N. Esposilo B, Onffilh E. Hcyd A. el II. Safely of in tlllvenOtlS ( ,proIlo1acin: I n:V\(W. AlMncan Journil of Med,(,ne 81 (Suppl. SA) 925-9 7S. 1989 An:ieri G. Griffith f. Gruen ..... ldt O. Heyd A. O'Brlen 8. et II. A survey of di nial up"nen.ce wilh ciprofloxaclll. 1 new qUillclone IntlmlCl'Oboll. JOtlrnl1 ofOinal Phlrmacolo&y 28: 179189. 1988 AmolT Gf. Kenll(l' C H. SJo.n RS. PoUllItz ST. Mulllplt-doK aproflOUCln k,neues III nonnal wbjectL ChnlClI PIIInnacoIOIlY Ind ThmIPCUlles 36: 384-388. 1984 A.-pi M. Glhrn- Hlnten B. Sopard p. BcnIZOn MW. COrnl*llIl'V( ,n v,tro ae11vllln of pdloo.tCln. olluuoeon. enoUoCln Ind ClP. rol'loUoCln 11111111 2S6 clinical 1SObtcs. AetI PJIIKJio&K:t MI crobtoIo&IaI el lrnrnu noIoI,Ica Sclnd'lIIIviCII Sea'on B 9S: 141146. 198) A$hby J. Piddock UV, WiK R. An invl'SliplIOn of the hyd~ p/'Iobteuy of lhe qllmolones. Journal of Anllrn,crobIll Chcrno. lherapy 16: SOS-808. 19S5 Auckentlltler R. MI(ho:l . H lrn~hpour M. Ptthere Jc. In vilro aclivlty of ~wtr qUlnoiones apinSiltCrobic baCteril. Journal of Antlrn i(robill Chemolhenlpy 17 (Suppl . 8): 29-39. 1986 AvenI CK. Knnskcy D. Kirlr.lin JK.. BourJe RC. Fill WD. SynelJisuc nep/'lrolOllC,ty due to ciprolloucin Ind ~Iospon n. American JOtlrnal of Med icine 8S: <4S2-4S3. 19&1 Awm WM. Oarbon J. GillY DRP. Detennilllluon ofaprolloxIC'in Ind lIS 1~h)knedlllrnine mnabolite in human M'fUrn Ind un"", loy hlah r-fonnanoe liquod domnu '''I1'''p/'Iy. Journal of Ool'Ollll\Oll1lp/'ly 4 I9: "14-420. 1911 !btl AP, FOl C, Ball ME. 8I'OWIIIRF. Wilhs JV . PtIIrmacolunoo.c. ,n volunlttn elies of oral ciprollo.ucin. II:)!)III Ind dda1y PlUcrtlL Journal of Antirnicrobial Chernotherapy 17: 629-63S. 1986 BaH P. CiprolloU(m: I n ovCfYiew of tdvCf1e up"nenen. Jour. l1li1 of Anlimiaobitl Cbemothcl1lpy 18 (StlppI . D~ 187·t93. 1986 BaTT)' AL, FI" RJ. Anllth JP. Oprollou(in di!l( , uS«p'Ibility tnt$: interpreti ve ~one sitt SLlndatdS for 31'. dites. Journal of Oi nictl MicrobiolO1Y 21: 880-883. 1985 BaTT)' AL, Jonn RN. In vilro activily of clprolloucin lIIinst J.I1Irn posItiVe coed. AlMrlcan JOtlrnal of Med icine 82: 27_32. 1981 Bany AL. Jones RN. ThomsbenyC, Ayen LW. Ger1lodt EH. et II. Anliblctcrill ae1lvities of apror1ouci n. noriIoUoCln. 0.0hnic Kid. anouan Ind IIIIlidn lC tad. AnlimlCrobial "FIllS Ind Chemotherapy n 633-63 •• 1984 8auernklnd A. ~tennlllltr C. In v,tro 1('11vily of ciprofloUoCln. norf\oUoCln llId IIIhd,u[ lad. Europo::an JOtlrMl of Q,nlCll' MicrobioIotY 2: til-I IS. 1983 Ba)'eT A. ~ A. Stephens M. Swt. JM . Pathy J. Pharrnaeokinel~ of Clprollo.ucin in the dda1y. Rl'l9lratoon 51: 292·29S. 1987 BecklTllnn J. ElsIsser w , Gunder!-Rerny U. Henlllrnpf R . Enoucin - I potenl inh ibilor of lbeop/'lyltine rneLlllohsrn. Eu~ p"ln Journal ofOin ia l PhtrmacolocY 33: 227·230. 1987 Bedard J. Charnberllnd S. w ons s, Schollaaardl T. Bryln LE. Conlribution of pcrmctbilily and KnsilivilY 10 inh ibi tion of DNA synthesis in detCTTllinl1ll w~tibllitlCS of 1::.K",.,.icItiQ coil. 1"st1MIomOllCIS IJt'nIgl1lOUl. Ind Aktlflv"n!ilf'(a/IJ 10 dp. mfloxlC'in. AntirnlCrObill Aatnllind Chcmotho:llIpy B: 14S714(>4, 1989 Bec:rmtnn D. Scholl H. WillFndcr w , I'onter D. Bellbler E. eI ... MCllboIitlll ofaprofloucill in min. In Nell" Weutl (&h) 1st Inlmlltioaal Ci~ucin Worbhop Prooeeainp, pp. 141_ 146. ~ MedICI, Arn$le1'dlrn. 1986 BendeT sw, Dl.lhofT A, ShIh PM. Slrehl R. Pouell H G. CiproIloucin ph.IrmlCOl
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Clinical PharmacokmCllcs ofC,proflOAacin
Iklpn T. Ddm C Johansen S. Kolslad 1M. Nord CEo CI al. Pharo macOkmCIIC$ of ciprollo~acin and effct't of repeated dOloage on s.al"a!) and fct'al mlcrollora. AntimICrobial Agents and Chcmotherap) 29 298·302. 1986b Ikrgan T. EngCloCl A. OISlc ..... sk, W. Os"by N. Solbell R. Pharo macokmcl1cs of clprollo,acon In j)("nphcral lymph and skin bhslc,..,. EurOj)("an Joumal ofChmcal MIC"Toblolog) 5: 458-461. 1986.3 Ikrgogne·lkrt/ln E. IkrthcJol G. E'cn P. Stern M. Rc)naud P Pcn~lralion of clprolloAacm ,mo bronchial loCCrelions. Eumj)("3n Journal ofChnl",1 I-hcrob'olos) 5: 197.200. 1986 Boelaert J. Vald( Y. Schurgcrs M. Danttls R. Rosseneu M. el 31 The pharmacokmelicsofClprolloAae,n 10 pallenls " -lih 1m· p'lIred ",nal funcl1on. Journal of Anllmlcroblal ChcmOlhcrap) 16: 87-93.1985 Boercma Jill. DalhofT A. Debru)nc FMY . Clprollo.ann d,w,· bUIiOn In proslallc IIssue and flUid follo",ng oral admonlslr.Ilion ChemOlhcrap)' 31- 11·18. 1985 Hocrcma JBJ. Debruyne FMJ. DalhofT A. InlraproslallC reneen1r.llIons of clprollo.acm aficr Inlravcnous admmlSlrallon, lancel' 695·696. 1984 Borner K l'qu,d ChrOmalography delcrmonallon of clprolloucm and some mctaoohles In human body Ilulds. Journal ofChnlcal Chcmisl!) and Chn,cal BIQ(:~m'SI!)' 24: 325-331. 1986 Borner K. HolThen G. lode H. Koeppe P. Prinzing C. el al. Pha rmacokonellcs of ciprollNacon in hcal1h) vOlunlttrs after oral and ,nlravcnous admln,slraIIOn. European Journal of Chnlcal Microbiology 5: 179-186. 1986a Bomer K. lode Ii. Hoff'ken G. Renal ellmonallon of sulfoc'proIlolacm. a new me'aool"c of coprollo,a,m. European Journal ofOmlcal Microbiology 5: 476. 1986b Bowles SK. Popovski Z. R}ook MJ. Beckman liB. Edwards DJ. el al. EfTttl of norllo\acon on Ihcoph)'lhne pharmacokmehcs al slcady,sLale. Anllmlcrob,al Agems and ChcmOlhcrap) 32 51()'512.1988 B05mar B. Edlund C Malmoorg ,\-5. Nord CEo Ciprolloueln concenlrallons and 'mpaCt of Ihe colon mlcmllora In pallcms undergo.ng colon:<:lal ~urgel1_ Anllmlcroblal Agenls and ChemOlherapy 34: 481-483. 1990 Brogard A_M. Jchl F. MonlCl1 H. Adloff M. Bllckle JF. el at Companson of high pressure hquld chromalll:$"'phy and mIcrobiologICal assay for the dClamma1l0n of blha!)' chmm· allon of clprolloncin In human~. AnllmlCrob,al Agents and Chemotherap) 28: 311-314. 1985a Brogard JM. Jelll F. Arnaud JP. Le,y P. Pelallan F. ct al . Oprolloxac1Oe: naluallon de son ':hm1Oallon blhare chez I"homme. Sch"'cIle"schc Medlllnosche Wochensehnft 115: 448-453. 1985b Brogard JM. MOn1e11 H. Jehl F. AdlofT M. Bllckle JF. Blhary ehm.nalion of ciprollo.acin ,n man: a comparali"e HPlC and microbIOlogical evaluallOn. In Rect'nI ad"ances .n chemoIherapy. IsII,pml J eds. AnumlC"Tob,al secuon 2. Procffdlngs of Ihe Fourteenlh Intemal10nal Conveu of Chemotherapy. K)olo. UnIversity of T okyo Prnt.. pp. 15g9.-1590. 199k BrJ,lmfil1 W. Franklin I. Grady D. Hamllton- M,lIer JMT. lliffe A. ChanU' In the pharmarokiocucs of ciprolloucin and fea.1 110111 during adminiSlralion ofa 1-
'oIun. leers. Anllmlcroblal Agenls and Chemolherapy 26: 131·761.
..
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Caekenbef1.he DlK, Panyn SR. In >'lIfO ICIlv lly of ciprOflo~ac1O compared wllh Ihose o f olher new Iluorinaled piperuinyl-subsiliuted quinolone derivlli>'C1. Anlimicrobial Agenls and Chemotherapy 25: 518·521. 1984 Campoli- Richards DM . Monk JP. Price A. Benfield P. Todd A. et al . CiprOllouci n; a reView of 1\$ anubaclenaJ 1CI1Vlly. pharmarokn>ttic j)fOpCT1lCS and lherapeullC usc. Orvp 35: 17J.447. 1988 Carbo M. ~ura J. ~ la TOm" R. !bdenls JM. Caml J . EffCCl of qUlnolones on caffclne dllpoSIUOn. Oinlal Pharmacology and Thel1lpeulics 4S: 234-240. 1989 Chalkley U . Koomhof HJ, Anllmlcroblal aclivily of cij)follo~3C1n apinsl PSt"Udomollw Ql'llIgmoJ:a. £SC'hpriciuQ coli. and Staplt,iOC'tXX'liS QUrftjJ delmTllned by lhe Iolh", curve melhod: anlibiotic rompanson and syne""su, Interactions. Anllmicrob,al Agents and C1
Ch,n N·X. Neu ftc. In ,·"ro aCI"-I ly of eno~ac,". a qUInolone caroo~)hc ac,d. compared wllh Ihose of norlloAlc,n. ne", bela· laclams. amlnogJycosldcs. and l"mClhopnm . Anumlcrob.al Agcms and ChemOlherap) 14: 75~.763. 1983 Chin N-X. Ncu ~IC. C,proflOUCln. a qumolone carboA)hc aCid compound aCII,e apmsl aerobiC and anacrob.c bacleria. Anll_ mlcrobl3l Agents and Cbemothcrapy 2S; 319-326. 1984 Chon N·X. Neu HC Post anub,onc suppresSl'-C effttl of c.proflo\ac,n agamsl gram j)OSlII'e a~d gram negall'e baetena. Ame"can Journal of Med'Clne 82: 58·62. 1987 Chu DTW. Fernandes PB. Chaloornc AK. Plhuleac E. Nordeen CWoel al. SymhCSls and slruclure·aClI' 11) fl"lallonshlps ofno"d af)llluorOQulnolone anubaCle"al ~genls. Journal of Moolc,nal Chem'SIl) 28: 1558·1564. 1985 CrJ,lmp B. Wise R. OI:nl J. PharmacoklnCllCS and lIssue peneu". 110n of clproflo\ann. Anllmicrobl.1 Agenls and Chemolherap)" 24 784-786. 1983 Cullmann W. SI1CJll1z M. !bars B. Oplcrkuch W. Comparal"'c evaluatIOn of recenll) de"cloped Qu,nolone compounds - wllh a nOle on the frequ~nC) of fl"S'SUni mutanls. ChemOlhcrap) 31; 19-28. 1985 DalhofT A. EiekenlX'rg H·U . Tissue d,stnbuhon of nprolloucm follOWIng oral and Inlra~cnous admlnlStrallon. Inf~1I0n I): 78-81, 1985 DalhofT A. We.dncr W. Diffusion of clprollo~a'm 1010 proslan, Iluid. European Journal ofOmlcal Mlcroblolog) 3; 36Q.362. 1994 Dan M. Golomb J. Gorea A. Braf Z. Ikrgcr SA. Concenlflll,on of coprollo~acm In human prOSla1lC Iissue afler oral admlms,o lrahon. Anllmlcrobl3l Agents and Chem01 herap) JO: 88-89. 1986 Dan M. Verbon N. Gorea A. Nagar H. Reller SA. ConcenlrallOns of clprolloucm m human h,·cr. gallbladder. and bile after oral admlnlSlra1l0n. European Journal ofChn.eal Ml crob'o lOiY 32: 211-218. 1987 Danielson 00. Grefbcrg N. N,I$$On P. WelS$ L WikStrom B. Renal CXCfl"lIon ofeiprolloxae. n. In Neu & Weuta (Eds) Firsl Inler. nallonal C.pmlloucm Workshop. uverkusen. pp. 127-129. Elcerpta MedICa. Amslerdam. 1985 DaloChner FD. W~ternfelder M. DalhofT A. Penelr.lllon of C'Prolloucm mlO kIdney. fat musele and skm llssue. European Journal ofChnlCal Mlcrob,ology 5: 212·213. 1986 DaVIS Rl. Kelly HW . Qucn~er RW. Slanderer J. Slembell B. el al. Effecl of norlloucon on Iheophylline metabohsm. Anll' microbial Agents and Chemolherapy 33: 212·214. 1989 DaVIS Rl. Koup JR. Wlillams-Warnn J. Weber A. Heggen l. el Bl. Pharmacokonellcs of ciprolloucm 10 c)"slic fibrosiS. Anl1' mlcroblll Agenls and Chemothenpy 31: 915·919.1987 D'ily rdallonships of Ihe qumolonc anllbac. tenals usmg the targel enzyme. The developmcnt and appllcalion of a DNA nrase aS$3y. Journal of Med,c,nal Chemlslry 29: 394-404. 1986 Dri1c. K. BioiOfY of bacterial deo~ynbonucleic aCid lopoisomerascs. MicrobiolO8kaI Revle....-s 48: 273·289, 1984 Drusano G L An overview oflhe phannacology of Intravenously adm'nislered ciprollo~acin. American Journal of Medlc.ne 82 (Suppl. 4A): 339-345. 1987 Dn.>sano GL Fonnl A. PlaIsance K. Glrjlan P. Yuen G. el al. Ciprolloucin hepalic handlin&- 271h Interscitnce Confen:nce on Anllmicrobial A&tnts and Chen".otherapy, Absll3C1 00. 1269. 1987b Dn.>sano GL Plaisance KI. Forrest A. Standiford He Dose rangins si udy and C(lnSt.anl infUSion evaluallon of cipf(llloucin. AnllmicrobiaJ AgenlS and Chemotherapy lO: 440----443. 1986a DruSllIlQ GL Standiford He. PLaisance K. Forresl A. Uthe J. el al. Absolule oral bioavallablilly of ciJ1'1"olloucin. Anlimicrobill "&CniS and Chemotherapy lO: 444-446. 19860 On.Isano GL WeIr M. Forresl A. Plaisance K. Emm T . et aJ.
Clin. Pharmarokmf'l. 19 (6) 199()
Pharmacoko~lln of Inll1l~enou'ily admlnlsLerrd elprono~acln In pallenl5 WII'" v.rlOUS Ikvtts o r ren.1 funcllon. AnLimi· crob.. 1 ASCnls and C'hcmoLllrnlpy 31: 860-864. 1987a Dudley M . Ericson J. Zin~r S H. EITn:ls of dose o n Soerum pharo macokint'l ics o f Inll1lVcnous dp"onolllCln WII'" ldenllficallon a nd chraclenUillon of ull'1lva~ular compartmenLs uSln& nonrompartmenlal and compartmental p.... rmarokint'lics models. Anllmlcrobial ASCnts .nd ChemOlllel'1lpy 3 1: 1782· 1786, 1987 Dudk'y MN . Pharmaroki~tic and pharmacod~namIC propertIeS of new qUlnokInc: anll-infcniva. HOSIlII.II Formulary 21 (Suppl. A): 9-lj. 1987 EliOpOUlos GM. Gardella A. Moellmn, RC. In Vllro K lIvily or elpronOlKln. a Mw carboay qU l nolo~ an\lmlCroblal .nl. AnumlCl'Obial AlienlS a nd CbemOlllcrapy H : 331·3)j. 19&4 EliOpOUlos GS. Mocllffln, AE. Reiu l'lrr E. Mocllmn, Jr RC. In Vllro IIIC1 IVI\IC1 of IIIe qULnolont' anllmtcroblalqrnls A·j6619 and A·S6620. Antimicrobial Aimts and (b,emotllcrapy 28: SI4nO.19U Elston RA . Tay lo r J . Possible interaction of dpfflnOlllcin wilh cyclo5porin A. Joumal of Anllmlcroblal ChcmOlllerapy 21: 679680. 1988 EsPO$ito S. Galan te D. Barba D. O'errico G. Mauone A. el a1. CipronoucLn concenLrations in human flUIds and LI"LIeS follow,", a s.mlk 01111 dose. Interna lional Joumal of Olnical PharmarolOlY Research 7: 181·186. 1987 Fal!in' N. DalholT A. WeuUl H. CiprolloAKln concenll1l1l0ns i n tonSI ls folio ..·,", a Slnlk inll1l vC'ROUS infUSIon. In l«lIon 12: lH-3S7. 1984 Fal!in' N. Dalhoff A. WeuUI H. Ciprollollleln conan ll1lllons in lonSlls follO"
functIOn. AnllmlCrobull Al£n1S and ClIcmothcnlpy 31: 709- 712. 1987 Gau W. Kun J, Ptttncn U. pjo,chke HJ . Wuen~he C lsolallon . nd stf\lC1ural elueidallon of unn3ry mct.abohlCll of elp"OnOA' ICln, An~imllld·Fonchun& 36: lS4S·1S49. 1986 Gellert M. DNA 10poisomel'1l~ Annual RevLC:w of 8locheml$lry SO: 879-9 10, 1981 Gellert M. Mlzuuchl K. O'Dea MH . Itoh T. TomlUwa JI. Nil· idilIC acu;! reSL,tance: a SfICOnd at~11C cl'llracter Invol~ed ,n DNA IYraSoe IIIC1IY lly. Proet~hnp ofllle Nallonal Academy of ~ofthc Unlled SUlles of Amcna 74: 4772..4116. 1977 GtnIIllCl'GJ. DalholT A. Weuta H. Sin&lc and muillple dose pharo macok iMlon 0( CLprofkUKln In 1YM~1 1ISSUC'5. Infl/C. lIOn 16 (Suppi. I): S24.528. 1988 Goldfarb J. Wonnser GP. InchlOSl Jr MA. GuiOcn G. Ow; M. el aI. SI~ pl'\IrmaookillClics of oral CLprollouccin in patlCnls wLlh cystic fibrosIs. Journal of(1Inocal Phlrm.arokJ&y 26: 222.226. 1986 Gonuk>: MA. MOI1Inchd AH. Duran S. Picl'llrdo A, Mqa na JL. el al. Muillpie dose pharmacokinelics o r ciprollo..ci n admln. iSlered Inlnvenously 10 normal volunteers. AntimICrobial ASC nlS and Chcmolhenpy 28: nS-2J9. 1985a Gonzalu MA. Monnchcl AH. Duran S. Pichardo A. Mqana JL. t l at Muhiple-dotc ciproflouci n dose nnlin! and kinellC$. O,nical PhlnnacoJosy Ind Tllcnpcul;cs 37: 6 3-637, 1985b Gonnlk>: MA. Unbe F. Moisen SD. Fus\CT AR. Selen A. el al. Multiple dose pha1lTllCOt1M11Ci 3nd safelY o r ciprofloucln in normal voluntCC1'S. AnllmK'T'ObiaI "&tntl and Chemotherapy 26: 741 .744. 1984 Goot.scns H. DeMoi P, COI~U H. ltV)' J . GI1Idos O. el al. Com· pll1IlIVe In ~l l ro at1IVIIICS of IZlrronllll. oprofloucln. nor· fIo.\lCln. olloUlcin. HR8I O (I new ~Iosponn). RN 2896S (I new macrohde). and otllcr .nts .,nsl entrropatlloifns. AnllmtcroblaJ ASCnl1 and ChcmothC1'lLpy 27: J83.392, Ig;U Gnbt M. FOfS&I\'n A. 8JOrk T . Concenlrallons of oprofloucin In SC1'\Im . nd prosUlIlC liHue in palirnlJ uncklJl)illl tl1lnsureIhl1ll rnIICIlon. EUfflpcan Journal of Oinocal Mlcrobi%&)' S: 211·212. 1986 Gnsda Jr TH , Schenl" JJ , Seelman AJ . WillOn JH . Thomal OJ. el al. InhIbition of enoudn Ibsorption by antacids or Iani· lidille. An timicrobial "&cnts and Chcmotllenpy B: 6 1 ~17. 1989 G~ire SL. (;"'Soela TH . FI't'C1' JP. Tack KJ . Schentq JJ . In· hlbilion of IMophylli~ clelra.nce l:7 co-administcrfdono..• CLn withoul alll'I1IllOn of tMophylhM elTccu. Anllmicroblal AlienlS Ind Chc:motllcrapy 31: 31S-378. 1987 Grimm H. In Vl tffl study with ciprofloucin: InlC1'j)ftUlIIVe CLi· lena of .... d,fl'U$IOI'I talloCC'Ordn" 10 sundan1s of the: NCCLS and DIN. Amrncan Journal of MedlClIIC 12 (Suppl. 4A): )76l3O, 1987 GUl y DRP. Awnl WM . ~el"$On PK. Obuj S. 8rel\enbuchcr R, elil. PharmaroklrIChCS ofelprofloUCIn In ICUtely III and con· Yalescrnl elderl y pallenls. American JOIIrnal of Medicine 82: 124- 129. 1987 GWly ORP. Awnl WM , Ptlcnon PK. Obtid S. Slein D. e l II. SIII&Ie and multiple dose phirmarokimt1cs of 01111 dproflo~· aein in elderly pltienls. In ternational Journal of Clmical Pharmacolo&y. TllcIlLPY Ind T oxicolo&Y 26: 279-2S4. 1988 H.lkin H. AdytTIC elTccu of lhe fluoroqllinoloncs. Revie;t.>s of Inftttiou, OiscaSCI 10 (Suppl. I): S2S8--S261 . 1988 Hant MW. Wood TH . £Jdtrl(lria coli KI2 mutants reSLstanllO nalidix iL" ~ ~tlC mappilll and dooilUlntt 1I!1dle$. Jour· naI of Bacttriolol)' 99: 238-241. 1969 Harder S. SUllb AH . Beer C. et al. 4-quinolones inhibil btotl1lnsJOnnalion of calTrinc. European Journal of Cllnocal PIwm· roIo&Y H: 6$1~S6. 198& Hn.ly DP, Polk RE. KalUlwali L. Rock DT, Mooney ML Inttr· lIIC1ion bel~n oral ciprofloudn atid c:a ffelM In nont\ll ~oIunteers. Anlimicrobial ASCnts and Cbcmolllel1py )3: 474478. 1989 Hil1li K,Aoyama H, lrikul1l T. Iyobe S. Mitsul'lllhi S. DIfferences in ,usctptibili ly 10 quinolonn of OUltr membnne mutants of SolmoMlfillyplrlmuT/um Ind Eschtr;clria roIi. Anlimicmbial ASCnls and Chc:mOlhuapy 29: HS-B8. 198N Hil1li K. Aoylma H. SUlue S. Inkun T. I)'obe S, et al. boiallOn
459
Clullcal Pharma cot.lIlt'UCS of Ciprono,acl~
and
char:lCl~n/allOn
of norno'ac,n n:S'Slanl mUlams of 1::5<"11-
(Or/chit) en" K·12 ..... nl'm'crob,al .... &'-"nls and Chemolhe",py
30:
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